| 1 | Mol. Psychiatry 2004 Nov 9: 981-3 |
|---|---|
| PMID | 15263908 |
| Title | Failure to confirm association between AKT1 haplotype and schizophrenia in a Japanese case-control population. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 2 | J Neural Transm (Vienna) 2004 Dec 111: 1583-92 |
| PMID | 15565492 |
| Title | Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. |
| Abstract | Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 3 | J Neural Transm (Vienna) 2004 Dec 111: 1583-92 |
| PMID | 15565492 |
| Title | Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients. |
| Abstract | Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 4 | Biol. Psychiatry 2004 Nov 56: 698-700 |
| PMID | 15522255 |
| Title | Association of AKT1 with schizophrenia confirmed in a Japanese population. |
| Abstract | Abnormality of the V-akt murine thymoma viral oncogene homologue 1 (AKT1) may be a predisposing factor in schizophrenia. Recent evidence supporting this hypothesis showed decreased AKT1 protein levels in patients with schizophrenia and significant association of AKT1 haplotypes according to the transmission disequilibrium test. We provide the first replication of this evidence using a relatively large case-control sample (507 Japanese schizophrenia and 437 control subjects). We genotyped five single nucleotide polymorphisms (SNPs) from the original study and one additional SNP. We found a positive association with an SNP (SNP5) different from the original study's findings (SNP3) and also significance in the haplotypes constructed from the combination of SNP5. Linkage disequilibrium around SNP5 was complex and may produce this positive association. Our study provides support for the theory that AKT1 is a susceptibility gene for Japanese schizophrenia. Fine linkage disequilibrium mapping is required for a conclusive result. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 5 | Nat. Genet. 2004 Feb 36: 131-7 |
| PMID | 14745448 |
| Title | Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. |
| Abstract | AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 6 | Schizophr. Res. 2004 Dec 71: 377-82 |
| PMID | 15474909 |
| Title | GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. |
| Abstract | The protein kinase glycogen synthase kinase-3 (GSK-3) is highly abundant in brain and involved in signal transduction cascades, particularly during neurodevelopment. We have previously found reduced GSK-3beta mRNA levels, protein levels and GSK-3 total (alpha+beta isoforms) activity in postmortem frontal cortex of schizophrenic patients in the Stanley Medical Research Institute's Brain Collection. To verify and extend these findings, GSK-3 parameters were now measured in the frontal cortex (BA9) and hippocampus obtained from the Rebecca L. Cooper Research Laboratories postmortem brain collection. Fifteen pairs of schizophrenic patients and matched control subjects have been studied. No significant differences in GSK-3alpha and GSK-3beta mRNA levels, GSK-3beta protein levels or total GSK-3 (alpha+beta) activity were found in the frontal cortex of the two diagnostic groups. Hippocampal GSK-3alpha and GSK-3beta mRNA levels were significantly lower (22% and 28%, respectively) in the tissue from the schizophrenic patients compared with the normal controls. Hippocampal GSK-3beta protein levels in the schizophrenic patients were 24% significantly lower than control values only after omission of three outlier subjects. Hippocampal total GSK-3 (alpha+beta) activity in the patients was 31% lower in the schizophrenic patients vs. control subjects. This difference was marginally significant. While our previous data on GSK-3beta in postmortem brain and the recent report that there is impaired AKT1-GSK-3beta signaling in schizophrenia suggest that changes in pathways involving protein kinases such as AKT1 and GSK-3beta in schizophrenia are complex, our present data do not provide strong evidence in support of the involvement of GSK-3beta in schizophrenia. Therefore, further investigation in a greater number of brain samples is warranted to better clarify the possible role of this enzyme in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 7 | Schizophr. Res. 2004 Dec 71: 377-82 |
| PMID | 15474909 |
| Title | GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. |
| Abstract | The protein kinase glycogen synthase kinase-3 (GSK-3) is highly abundant in brain and involved in signal transduction cascades, particularly during neurodevelopment. We have previously found reduced GSK-3beta mRNA levels, protein levels and GSK-3 total (alpha+beta isoforms) activity in postmortem frontal cortex of schizophrenic patients in the Stanley Medical Research Institute's Brain Collection. To verify and extend these findings, GSK-3 parameters were now measured in the frontal cortex (BA9) and hippocampus obtained from the Rebecca L. Cooper Research Laboratories postmortem brain collection. Fifteen pairs of schizophrenic patients and matched control subjects have been studied. No significant differences in GSK-3alpha and GSK-3beta mRNA levels, GSK-3beta protein levels or total GSK-3 (alpha+beta) activity were found in the frontal cortex of the two diagnostic groups. Hippocampal GSK-3alpha and GSK-3beta mRNA levels were significantly lower (22% and 28%, respectively) in the tissue from the schizophrenic patients compared with the normal controls. Hippocampal GSK-3beta protein levels in the schizophrenic patients were 24% significantly lower than control values only after omission of three outlier subjects. Hippocampal total GSK-3 (alpha+beta) activity in the patients was 31% lower in the schizophrenic patients vs. control subjects. This difference was marginally significant. While our previous data on GSK-3beta in postmortem brain and the recent report that there is impaired AKT1-GSK-3beta signaling in schizophrenia suggest that changes in pathways involving protein kinases such as AKT1 and GSK-3beta in schizophrenia are complex, our present data do not provide strong evidence in support of the involvement of GSK-3beta in schizophrenia. Therefore, further investigation in a greater number of brain samples is warranted to better clarify the possible role of this enzyme in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 8 | Biol. Psychiatry 2005 Sep 58: 446-50 |
| PMID | 16026766 |
| Title | Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. |
| Abstract | Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample. We investigated the reported association of DNA sequence variants in the AKT1 gene in a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported. We obtained statistical significance for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study. The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 9 | Biol. Psychiatry 2005 Sep 58: 446-50 |
| PMID | 16026766 |
| Title | Further evidence for association of variants in the AKT1 gene with schizophrenia in a sample of European sib-pair families. |
| Abstract | Involvement of AKT signaling pathways in schizophrenia has been recently suggested, on the basis of several lines of evidence. In addition to impairment of protein-levels and phosphorylation levels in the pathway, association of DNA sequence variants in the AKT1 gene with schizophrenia has been detected in a family sample. We investigated the reported association of DNA sequence variants in the AKT1 gene in a sample of 79 sib-pair families with schizophrenia using the five single nucleotide polymorphisms (SNPs) of the original study and two additional SNPs in the neighborhood of the SNP for which association had been reported. We obtained statistical significance for single markers (p = .002) and multilocus haplotypes (p = .0013) located in the same region as has been reported in the previous study. The replication of association of variants in the AKT1 gene in a family sample with similar ethnical background as in the original study adds further evidence for involvement of AKT1 in development of schizophrenic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 10 | Proc. Natl. Acad. Sci. U.S.A. 2006 Nov 103: 16906-11 |
| PMID | 17077150 |
| Title | Akt1 deficiency affects neuronal morphology and predisposes to abnormalities in prefrontal cortex functioning. |
| Abstract | There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. We asked whether AKT1 deficiency in mice results in structural and functional abnormalities in prefrontal cortex (PFC). Exploratory transcriptional profiling revealed concerted alterations in the expression of PFC genes controlling synaptic function, neuronal development, myelination, and actin polymerization, and follow-up ultrastructural analysis identified consistent changes in the dendritic architecture of pyramidal neurons. Behavioral analysis indicated that AKT1-mutant mice have normal acquisition of a PFC-dependent cognitive task but abnormal working memory retention under neurochemical challenge of three distinct neurotransmitter systems. Thus, AKT1 deficiency creates a context permissive for gene-gene and gene-environment interactions that modulate PFC functioning and contribute to the disease risk associated with this locus, the severity of the clinical syndrome, or both. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 11 | Eur. J. Hum. Genet. 2006 Jun 14: 669-80 |
| PMID | 16721403 |
| Title | Molecular genetic studies of schizophrenia. |
| Abstract | The study of schizophrenia genetics has confirmed the importance of genes in etiology, but has not so far identified the relationship between observed genetic risks and specific DNA variants, protein alterations or biological processes. In spite of many limitations, numerous regions of the human genome give consistent, although by no means unanimous, support for linkage, which is unlikely to occur by chance. Two recent shifts have been evident in the field. First, a series of studies combining linkage and association analyses in the same family sets have identified promising candidate genes (DTNBP1, NRG1, G72/G30, TRAR4). Although a consensus definition of replication for genetic association in a complex trait remains difficult to achieve, the evidence for two of these (dystrobrevin binding protein 1 (DTNBP1), NRG1) is strong. Second, a series of studies combining association with functional investigation of changes in the associated gene in schizophrenia have also identified several candidate genes (COMT, RGS4, PPP3CC, ZDHHC8, AKT1). Somewhat surprisingly, the loci implicated by these studies have proven less robust in replication, although the number of replication studies remains small in several cases. Assessment of the combined evidence for the DTNBP1 gene gives some insight into the nature of the problems remaining to be solved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 12 | Dialogues Clin Neurosci 2006 -1 8: 79-84 |
| PMID | 16640117 |
| Title | Clinical impact of recently detected susceptibility genes for schizophrenia. |
| Abstract | After years of frustration, the search for genes impacting on schizophrenia is now undergoing some exciting developments. Several proposals of susceptibility genes have been able to be supported by replications. Thus, there are now at least three very strong candidates: the gene for dysbindin (DTNBP1), the gene for neuregulin-1 (NRG1), and a less well-understood gene locus, G72/G30, which are likely to influence manifestations of schizophrenia. Other "hot" candidates such as the disrupted-in-schizophrenia 1 gene (DISC1) and the gene coding for protein kinase B (AKT1) might also prove to be susceptibility genes in the next future. The clinical implications of these findings are not yet fully visible. However, some first insights are possible: most of the genetic findings lack diagnostic specificity, and are also reproduced in bipolar disorder. Strong associations are also obtained on a symptomatic level, not only on a diagnostic level. The pathophysiological role of these hot candidate genes is currently under intensive study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 13 | Curr Opin Psychiatry 2006 Mar 19: 158-64 |
| PMID | 16612196 |
| Title | An update on the genetics of schizophrenia. |
| Abstract | This paper reviews recent molecular genetic studies of schizophrenia and evaluates claims implicating specific genes as susceptibility loci. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and the evidence is accumulating in favour of several positional candidate genes. Currently, the strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1). For other genes, disrupted in schizophrenia (DISC1), D-amino acid oxidase activator (DAOA), regulator of G-protein signalling 4 (RGS4) and V-AKT murine thymoma viral oncogene homolog 1 (AKT1) the data are promising but not yet compelling. In the most convincing cases, the risk haplotypes appear to be associated with small effect sizes and do not fully explain the linkage findings that prompted each study. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research. Despite the accumulation of significant genetic data, however, the susceptibility variants have yet to be identified and detailed follow-up studies are now required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 14 | Psychiatr. Genet. 2006 Feb 16: 39-41 |
| PMID | 16395129 |
| Title | Absence of significant associations between four AKT1 SNP markers and schizophrenia in the Taiwanese population. |
| Abstract | AKT1 (V-akt murine thymoma viral oncogene homolog 1) is a protein kinase isoform of AKT. Five single-nucleotide polymorphisms, rs3803300, rs1130214, rs3730358, rs2498799 and rs2494732, at the genomic region of AKT1 have been reported to be significantly associated with schizophrenia. We tested for the presence of these five single-nucleotide polymorphisms in a Taiwanese population by genotyping 218 co-affected schizophrenia families. Both single locus and haplotypes analyses showed no association of these single-nucleotide polymorphisms with schizophrenia. These findings fail to support AKT1 as a susceptibility gene for schizophrenia in the Taiwanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 15 | Int. J. Neuropsychopharmacol. 2006 Feb 9: 77-81 |
| PMID | 15982448 |
| Title | Positive association of AKT1 haplotype to Japanese methamphetamine use disorder. |
| Abstract | Recent evidence suggests that the AKT1-GSK3beta signalling cascade partially mediates dopamine-dependent behaviours. In relation to the pathophysiology of schizophrenia or methamphetamine (Meth) use disorder, AKT1 is a good candidate gene for such conditions. For schizophrenia, positive associations of SNPs and AKT1 haplotypes were reported in US and Japanese samples. To evaluate the association between AKT1 and Meth-use disorder, we conducted a case-control study of Japanese samples (182 patients and 437 controls). A positive association between a SNP and haplotypes was found, and the 'signal' SNP was the same SNP found to be associated with US schizophrenia, but not with Japanese schizophrenia. Our results indicate that AKT1 may play a possible role in the development of Meth-use disorder. Further investigation of these associations, together with evidence from previous animal studies, may open the way to elucidation of the pathophysiology of this condition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 16 | J. Neurochem. 2006 Oct 99: 277-87 |
| PMID | 16987250 |
| Title | Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia. |
| Abstract | The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 17 | Eur. J. Hum. Genet. 2006 Sep 14: 1037-43 |
| PMID | 16736033 |
| Title | A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. |
| Abstract | In order to explore the role of noncoding variants in the genetics of schizophrenia, we sequenced 27 kb of noncoding DNA from the gene loci RAC-alpha serine/threonine-protein kinase (AKT1), brain-derived neurotrophic factor (BDNF), dopamine receptor-3 (DRD3), dystrobrevin binding protein-1 (DTNBP1), neuregulin-1 (NRG1) and regulator of G-protein signaling-4 (RGS4) in 37 schizophrenia patients and 25 healthy controls. To compare the allele frequency spectrum between the two samples, we separately computed Tajima's D-value for each sample. The results showed a smaller Tajima's D-value in the case sample, pointing to an excess of rare variants as compared to the control sample. When randomly permuting the affection status of sequenced individuals, we observed a stronger decrease of Tajima's D in 2400 out of 100,000 permutations, corresponding to a P-value of 0.024 in a one-sided test. Thus, rare variants are significantly enriched in the schizophrenia sample, indicating the existence of disease-related sequence alterations. When categorizing the sequenced fragments according to their level of human-rodent conservation or according to their gene locus, we observed a wide range of diversity parameter estimates. Rare variants were enriched in conserved regions as compared to nonconserved regions in both samples. Nevertheless, rare variants remained more common among patients, suggesting an increased number of variants under purifying selection in this sample. Finally, we performed a heuristic search for the subset of gene loci, which jointly produces the strongest difference between controls and cases. This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4. Taken together, our approach provides promising strategy to investigate the genetics of schizophrenia and related phenotypes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 18 | J. Neurochem. 2006 Oct 99: 277-87 |
| PMID | 16987250 |
| Title | Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia. |
| Abstract | The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 19 | J. Neurochem. 2006 Oct 99: 277-87 |
| PMID | 16987250 |
| Title | Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia. |
| Abstract | The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 20 | Schizophr. Res. 2006 Jun 84: 253-71 |
| PMID | 16632332 |
| Title | Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. |
| Abstract | Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jun 141B: 383-6 |
| PMID | 16583435 |
| Title | Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. |
| Abstract | AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 22 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jun 141B: 383-6 |
| PMID | 16583435 |
| Title | Association of AKT1 haplotype with the risk of schizophrenia in Iranian population. |
| Abstract | AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 23 | Schizophr. Res. 2007 Mar 91: 27-36 |
| PMID | 17300918 |
| Title | The role of DTNBP1, NRG1, and AKT1 in the genetics of schizophrenia in Finland. |
| Abstract | Several putative schizophrenia susceptibility genes have recently been identified. Significant associations between schizophrenia and neuregulin 1 (NRG1) and dysbindin (DTNBP1) were first reported in 2002 and studies in several populations have since independently reported positive associations to these gene regions. Further, both tentative functional and genetic data have implicated the role of AKT1 in the genetic background of this disorder. However, findings have not been consistent in all populations. We investigated the allelic diversity of these three genes NRG1, DTNBP1 and AKT1 in a representative nation-wide study sample of 441 Finnish schizophrenia families consisting of 865 affected individuals, in order to assess their role in one of the largest population-based study samples. DTNBP1 and AKT1 failed to show evidence of association, whereas two SNPs in the 3' region of the NRG1 gene yielded suggestive evidence of association (p=0.012 and p=0.048) in family-based association analyses. Thus, our study does not indicate that AKT1 or DTNBP1 play a role in the etiology of schizophrenia in the Finnish population. Furthermore, results do not support a major role for NRG1, but we cannot completely exclude a minor role of this gene in the Finnish population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 24 | Genes Brain Behav. 2007 Feb 6: 107-12 |
| PMID | 17233643 |
| Title | Possible association of beta-arrestin 2 gene with methamphetamine use disorder, but not schizophrenia. |
| Abstract | Recent investigations suggest that the AKT/glycogen synthase kinase 3 (GSK3) signaling cascade may be associated with the pathophysiology of schizophrenia and methamphetamine (METH) use disorder. One important molecule related to this cascade is beta-arrestin 2 (ARRB2). We therefore conducted a genetic case-control association analysis of the gene for ARRB2 with schizophrenia and METH use disorder in a Japanese population (547 people with schizophrenia, 177 with METH use disorder and 546 controls). A possible association of 'tag single nucleotide polymorphisms (SNPs)' was found in METH use disorder (rs1045280: P(genotype) = 0.0118, P(allele) = 0.00351; rs2036657: P(allele) = 0.0431; rs4790694: P(genotype) = 0.0167, P(allele) = 0.0202), but no association was found with schizophrenia. We also evaluated the gene-gene interactions among ARRB2, AKT1, and GSK3B, which we previously reported for each of these diseases. However, no interaction was seen in our samples. This is the first association analysis of ARRB2, and our results indicate that ARRB2 may play a role in the pathophysiology of METH use disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 25 | PLoS ONE 2007 -1 2: e1369 |
| PMID | 18159252 |
| Title | Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer. |
| Abstract | Neuregulin-1 (NRG1) is a putative schizophrenia susceptibility gene involved extensively in central nervous system development as well as cancer invasion and metastasis. Using a B lymphoblast cell model, we previously demonstrated impairment in NRG1alpha-mediated migration in cells derived from patients with schizophrenia as well as effects of risk alleles in NRG1 and catechol-O-methyltransferase (COMT), a second gene implicated both in schizophrenia susceptibility and in cancer. Here, we examine cell adhesion, an essential component process of cell motility, using an integrin-mediated cell adhesion assay based on an interaction between ICAM-1 and the CD11a/CD18 integrin heterodimer expressed on lymphoblasts. In our assay, NRG1alpha induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. The maximum range of variation in adhesion over sixty minutes correlates strongly with NRG1alpha-induced migration (r(2) = 0.61). NRG1alpha-induced adhesion variation is blocked by erbB2, PI3K, and Akt inhibitors, but not by PLC, ROCK, MLCK, or MEK inhibitors, implicating the erbB2/PI3K/AKT1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 patients with schizophrenia and 20 normal controls, cells from patients show a significant deficiency in the range of NRG1alpha-induced adhesion (p = 0.0002). In contrast, the response of patient-derived cells to phorbol myristate acetate is unimpaired. The COMT Val108/158Met genotype demonstrates a strong trend towards predicting the range of the NRG1alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in normal subjects (p = 0.063). Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 26 | J Clin Psychiatry 2007 Sep 68: 1358-67 |
| PMID | 17915974 |
| Title | Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population. |
| Abstract | A number of studies have pointed to the involvement of AKT signaling pathways in the etiology of schizophrenia. The purpose of this study was to determine whether the AKT1 gene is involved in the etiology of schizophrenia and whether it affects therapeutic outcomes in the Chinese population. Five single nucleotide polymorphisms (SNPs) were genotyped among 384 schizophrenic patients (DSM-IV criteria) and 384 healthy controls from the Chinese population. We systematically analyzed the association of the AKT1 gene with schizophrenia on the basis of sex, age at onset, therapeutic response to typical antipsychotics and atypical antipsychotics, and presence or absence of extrapyramidal syndrome. The study was conducted from May 2004 to June 2006. We found a positive association of the G allele of the SNP marker rs3803300 with schizophrenia (p = .003), both in early-onset and late-onset subjects, and that a haplotype A-G-C-G-A constructed by the 5 SNPs showed significant association (p = .00004886). However, we found no relationship between any of the 5 SNP markers and therapeutic response to typical and atypical antipsychotics and chlorpromazine-induced extrapyramidal syndrome. Our study suggests that AKT1 is a susceptibility gene for schizophrenia in the Chinese population and that the AKT1 gene may play no major role in the therapeutic response to antipsychotics or in chlorpromazine-induced extrapyramidal syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 27 | Aust N Z J Psychiatry 2007 Feb 41: 169-77 |
| PMID | 17464696 |
| Title | AKT1 and neurocognition in schizophrenia. |
| Abstract | Previous research has shown conflicting results for the significance of five v-akt murine thymoma viral oncogene homolog 1 (AKT1) single-nucleotide polymorphisms (SNPs) to the aetiology of schizophrenia. Neurocognition is a plausible endophenotype for schizophrenia and it was reasoned that the lack of agreement might be due to variability in neurocognition across studies. Therefore, the association of genetic variation in AKT1 with neurocognition was investigated in patients with schizophrenia. The same five SNPs used in previous studies of the etiology of schizophrenia (rs2494732, rs2498799, rs3730358, rs1130214, [corrected] and rs3803300) were genotyped in 641 individuals with schizophrenia who had participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. The primary dependent variable was a neurocognitive composite score and exploratory analyses investigated five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance). There were no significant asymptotic or empirical associations between any SNP and the neurocognitive composite score. The authors also investigated the association of five-SNP haplotypes with the neurocognitive composite score. A marginally significant association was observed for the neurocognitive composite score with one of the five-SNP haplotypes (global score statistic 19.51, df = 9, permutation p = 0.02). Exploratory analyses of five domain scores (processing speed, reasoning, verbal memory, working memory, and vigilance) were non-significant for all five SNPs. Results published to date for an association between genetic variation in AKT1 with schizophrenia are inconsistent. The results suggest that the AKT1 markers studied are not associated with neurocognition in schizophrenia, and do not support unassessed variation in neurocognitive scores as a reason for this discrepancy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 28 | Schizophr. Res. 2007 Jul 93: 58-65 |
| PMID | 17383860 |
| Title | Association analysis of AKT1 and schizophrenia in a UK case control sample. |
| Abstract | AKT1 (V-akt murine thyoma viral oncogene homolog 1) is involved in intracellular signalling pathways postulated as of aetiological importance in schizophrenia. Markers in the AKT1 gene have also recently been associated with schizophrenia in two samples of European origin and in Japanese and Iranian samples. Aiming to replicate these findings, we examined ten SNPs spanning AKT1 in a UK case-control sample (schizophrenia cases n=673, controls n=716). These included all SNPs previously reported to be associated in European, Japanese and Iranian samples, alone or in haplotypes, as well as additional markers defined by the Haploview Tagger program (pair-wise tagging, minimum r(2)=0.8, minor allele frequency=0.02). We found no association with single markers (min p=0.17). We found weak evidence for association (p=0.04) with a four marker haplotype reported as significant in the original positive European sample of Emamian et al. [Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A., 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131-137] and also an overlapping three marker haplotype (p=0.016) that had previously been reported as significant in a Japanese sample. Nominal p-values for these haplotypes did not survive correction for multiple testing. Our study provides at best weak support for the hypothesis that AKT1 is a susceptibility gene for schizophrenia. Examination of our own data and those of other groups leads us to conclude that overall, the evidence for association of AKT1 as a susceptibility gene for schizophrenia is weakly positive, but not yet convincing. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 29 | Schizophr Bull 2007 Nov 33: 1343-53 |
| PMID | 17329232 |
| Title | eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? |
| Abstract | Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 30 | J Clin Psychiatry 2007 Sep 68: 1358-67 |
| PMID | 17915974 |
| Title | Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population. |
| Abstract | A number of studies have pointed to the involvement of AKT signaling pathways in the etiology of schizophrenia. The purpose of this study was to determine whether the AKT1 gene is involved in the etiology of schizophrenia and whether it affects therapeutic outcomes in the Chinese population. Five single nucleotide polymorphisms (SNPs) were genotyped among 384 schizophrenic patients (DSM-IV criteria) and 384 healthy controls from the Chinese population. We systematically analyzed the association of the AKT1 gene with schizophrenia on the basis of sex, age at onset, therapeutic response to typical antipsychotics and atypical antipsychotics, and presence or absence of extrapyramidal syndrome. The study was conducted from May 2004 to June 2006. We found a positive association of the G allele of the SNP marker rs3803300 with schizophrenia (p = .003), both in early-onset and late-onset subjects, and that a haplotype A-G-C-G-A constructed by the 5 SNPs showed significant association (p = .00004886). However, we found no relationship between any of the 5 SNP markers and therapeutic response to typical and atypical antipsychotics and chlorpromazine-induced extrapyramidal syndrome. Our study suggests that AKT1 is a susceptibility gene for schizophrenia in the Chinese population and that the AKT1 gene may play no major role in the therapeutic response to antipsychotics or in chlorpromazine-induced extrapyramidal syndrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 31 | Pharmacogenomics 2008 Oct 9: 1437-43 |
| PMID | 18855532 |
| Title | Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. |
| Abstract | Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia. A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale. Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone. These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 32 | Schizophr. Res. 2008 Dec 106: 248-52 |
| PMID | 18838251 |
| Title | Genetic study of eight AKT1 gene polymorphisms and their interaction with DRD2 gene polymorphisms in tardive dyskinesia. |
| Abstract | Tardive dyskinesia (TD) is a motor adverse effect of chronic antipsychotic medication. It has been suggested to involve dopamine neurotransmission system changes. AKT1 acts downstream of the D(2) receptor that is blocked by all antipsychotics to some degree. The AKT1 gene has not been investigated in TD. We examined eight polymorphisms spanning the AKT1 gene and their association with TD in our schizophrenia sample of 193 Caucasians, 76 of which with TD. AKT1 polymorphisms and haplotypes were not significantly associated with TD. However, we detected a significant interaction between rs6275 of DRD2 and rs3730358 of AKT1 (p<1 x 10(-5)). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 33 | Neurosci. Lett. 2008 May 436: 232-4 |
| PMID | 18395980 |
| Title | Association between AKT1 gene and Parkinson's disease: a protective haplotype. |
| Abstract | Variation in AKT1 has been associated with schizophrenia, bipolar disease and type II diabetes. The aim of the present study was to investigate the potential role of variability within AKT1 as a risk factor for Parkinson's disease (PD). We performed a case-control association analysis of AKT1 in a Greek cohort of PD using four tagging SNPs and five constructed haplotypes. To assess the structure of this locus in different populations we have performed linkage disequilibrium (LD) analysis using these variants [dunning]. In multilocus analysis, the frequency of a four-SNP1/2/3/4 haplotype was significantly higher in controls in comparison with PD patients (chi(2)=19.76, p=0.00009, OR=0.11 C.I.=0.03-0.35). The association remained significant even after Bonferroni correction for the number of haplotypes (p=0.0002). So, this certain haplotype was significantly associated with reduced risk of the disease. The data presented here suggest the involvement of AKT1 in protection of PD through many possible mechanisms involving different signaling pathways that could be potential therapeutic targets in the future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 34 | Mol. Psychiatry 2008 Sep 13: 873-7 |
| PMID | 18195713 |
| Title | Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. |
| Abstract | The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 35 | J. Clin. Invest. 2008 Jun 118: 2200-8 |
| PMID | 18497887 |
| Title | Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans. |
| Abstract | AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 36 | Biol. Psychiatry 2008 Sep 64: 438-42 |
| PMID | 18466879 |
| Title | Association of a nonsynonymous variant of DAOA with visuospatial ability in a bipolar family sample. |
| Abstract | Bipolar disorder and schizophrenia are hypothesized to share some genetic background. In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA, COMT, DTNBP1, NRG1, and AKT1, on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder. In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 x 10(-6) and 5 x 10(-6), respectively) (n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait. The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 37 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 38 | Biol. Psychiatry 2008 Mar 63: 449-57 |
| PMID | 17825267 |
| Title | AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. |
| Abstract | The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. The association of DTNBP1 in the Irish Study of High Density schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5' end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 39 | Int. J. Neuropsychopharmacol. 2008 Mar 11: 197-205 |
| PMID | 17681085 |
| Title | Possible involvement of post-dopamine D2 receptor signalling components in the pathophysiology of schizophrenia. |
| Abstract | Par-4 has been suggested to mediate dopamine neurotransmission. Dopamine D2 receptor (DRD2) activation induces a signalling complex of AKT1, PP2A and beta-arrestin2 which dephosphorylates/inactivates AKT1 thereby activating GSK-3beta, transducing dopamine-dependent behaviour. DRD2 activation also results in down-regulation of PKA activity. Among other substrates PKA phosphorylates GSK-3beta. Prolonged DRD2 activation leads to its 'desensitization' which involves GRKs and beta-arrestins. beta-arrestin1 binds to phosphorylated receptors preventing further G-protein stimulation. This study examined whether Par-4, beta-arrestin1, AKT1 and GSK-3beta are involved in the pathophysiology of schizophrenia. Lymphocytes obtained from schizophrenia and bipolar patients and healthy controls recruited from the Beer-Sheva Mental Health Center were transformed by Epstein-Barr virus (EBV) into lymphocyte-derived cell lines (LDCL). Post-mortem brain samples were obtained from the Rebecca L. Cooper Brain Bank, Parkville, Australia. The study was approved by the IRB committees of Beer-Sheva, Israel and Parkville, Australia. Levels of the specific proteins were assayed by Western blotting. beta-arrestin1 protein levels were significantly ~2-fold increased in LDCL from schizophrenia patients while Par-4 protein levels were unaltered. A 63% significant decrease was found in frontal cortex phospho-Ser9-GSK-3beta protein levels in schizophrenia but not in those of AKT1, Par-4 or beta-arrestin1. Elevated beta-arrestin1 protein levels in LDCL and decreased phospho-Ser9-GSK-3beta protein levels in post-mortem frontal cortex of schizophrenia patients vs. control groups support the possible involvement of these proteins in the pathophysiology of schizophrenia. However, since we did not find differences in beta-arrestin1, AKT1 and Par-4 protein levels in post-mortem frontal cortex of schizophrenia patients and although GSK-3beta participates in other signalling cascades we can not rule out the possibility that the differences found reflect deviation in DRD2 signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 40 | Biol. Psychiatry 2008 Mar 63: 449-57 |
| PMID | 17825267 |
| Title | AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. |
| Abstract | The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients. The association of DTNBP1 in the Irish Study of High Density schizophrenia Families (ISHDSF) prompted our investigation of AKT1 for association with disease in this sample. Eight single nucleotide polymorphisms spanning AKT1 were analyzed for association with schizophrenia across four definitions of affection and according to Operational Criteria Checklist of Psychotic Illness (OPCRIT) symptom scales. We examined expression of AKT1 messenger RNA from postmortem brain tissue of schizophrenic, bipolar, and control individuals. No single marker showed significant association, but the risk haplotype previously found over-transmitted to Caucasian schizophrenic patients was significantly under-transmitted in the ISHDSF (.01 < p < .05), across all OPCRIT symptom dimensions. Exploratory haplotype analysis confirmed association with schizophrenia toward the 5' end of AKT1 (.008 < p < .049, uncorrected). We found significantly decreased RNA levels in prefrontal cortex of schizophrenic individuals, consistent with reduced AKT1 protein levels reported in schizophrenic brain. The replication of association of AKT1 gene variants in a further Caucasian family sample adds support for involvement of AKT signaling in schizophrenia, perhaps encompassing a broader clinical phenotype that includes mood dysregulation. We show that AKT signaling might be compromised in schizophrenic and bipolar patients via reduced RNA expression of specific AKT isoforms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 41 | Psychiatry Investig 2009 Jun 6: 102-7 |
| PMID | 20046382 |
| Title | AKT1 Gene Polymorphisms and Obstetric Complications in the Patients with Schizophrenia. |
| Abstract | We performed a genetic association study with schizophrenic patients to investigate whether the V-akt murine thymoma viral oncogene homolog 1 (AKT1) gene plays a role in obstetric complications. One-hundred-eighty patients with schizophrenia (male, 113; female, 67) were included. All patients fulfilled DSM-IV criteria for schizophrenia. Obstetric complications were measured by the Lewis scale. Prenatal and perinatal information was retrospectively collected from the patients' mothers. We selected six single nucleotide polymorphisms (SNPs) for the AKT1 gene: SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs 1130233), SNP5 (rs2494732), and SNPA (rs2498804). The genotype data were analyzed for an association with the Lewis total score in terms of allele, genotype, and haplotype distribution. The mean total Lewis scores were 1.30+/-1.61 for males and 1.54+/-1.87 for females. Higher total score tended to be correlated with an earlier age of onset of schizophrenia in females. In the total sample, no SNP was associated with obstetric complications. However, the additional analyses for male and female subgroups found a significant association between SNPA and SNP4 and Lewis score in females (p=0.02 for SNPA, p=0.04 for SNP4). The SNP5-SNPA haplotype showed a positive association with obstetric complications (p=0.03) in the female patient group. We found an association between SNPs in the AKT1 gene and total Lewis score measuring obstetric complications in female patients with schizophrenia. Because these findings did not survive a correction for multiple testing, the significance should be interpreted carefully and replication studies are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 42 | Cogn Neuropsychiatry 2009 -1 14: 277-98 |
| PMID | 19634031 |
| Title | Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms. |
| Abstract | schizophrenia has complex genetic heritability. It is also genetically heterogeneous. To the extent that genes are associated with symptom constellations in schizophrenia, they do so by affecting the development and function of neural systems that mediate the expression of such diverse behavioral, cognitive and perceptual phenomena. The genetic mechanisms of human brain dysfunction remain to be well understood. "Imaging genetics" is an emerging field that attempts to integrate the basic biology of putative disease mechanisms with physiological correlates from the live human brain. Here, we review recent imaging genetics work on prefrontal brain systems associated with working memory and executive function - heritable traits relevant to schizophrenia. Starting with genetic variation in dopaminergic systems (e.g., COMT), we examined the modulation of prefrontal brain networks during active cognitive processing; there is also evidence that variation in the expression of dopamine-related downstream intra-cellular signaling molecules (e.g., AKT1) are implicated. Moreover, these genetic variants evidence epistasis on neuroimaging measures, lending further support to the conceptualization that non-additive combinations of multiple genes modulate active human cognitive brain mechanisms. The imaging genetics platform therefore could extend understanding of genetic mechanisms of human cognitive brain processes relevant to neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 43 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 44 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jul 150B: 683-92 |
| PMID | 19051289 |
| Title | Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins. |
| Abstract | AKT1, encoding the protein kinase B, has been associated with the genetic etiology of schizophrenia and bipolar disorder. However, minuscule data exist on the role of different alleles of AKT1 in measurable quantitative endophenotypes, such as cognitive abilities and neuroanatomical features, showing deviations in schizophrenia and bipolar disorder. We evaluated the contribution of AKT1 to quantitative cognitive traits and 3D high-resolution neuroanatomical images in a Finnish twin sample consisting of 298 twins: 61 pairs with schizophrenia (8 concordant), 31 pairs with bipolar disorder (5 concordant) and 65 control pairs matched for age, sex and demographics. An AKT1 allele defined by the SNP rs1130214 located in the UTR of the gene revealed association with cognitive traits related to verbal learning and memory (P = 0.0005 for a composite index). This association was further fortified by a higher degree of resemblance of verbal memory capacity in pairs sharing the rs1130214 genotype compared to pairs not sharing the genotype. Furthermore, the same allele was also associated with decreased gray matter density in medial and dorsolateral prefrontal cortex (P < 0.05). Our findings support the role of AKT1 in the genetic background of cognitive and anatomical features, known to be affected by psychotic disorders. The established association of the same allelic variant of AKT1 with both cognitive and neuroanatomical aberrations could suggest that AKT1 exerts its effect on verbal learning and memory via neural networks involving prefrontal cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 45 | J. Psychopharmacol. (Oxford) 2009 Nov 23: 937-43 |
| PMID | 18635704 |
| Title | Lack of association between AKT1 variances versus clinical manifestations and social function in patients with schizophrenia. |
| Abstract | The elucidation of genotype-phenotype relationships in psychiatric research is at an early stage. V-akt murine thymoma viral oncogene homolog 1 (AKT1) is a serine/threonine kinase known as protein kinase B. Emerging studies have implicated the role of AKT1 in pathogenesis of schizophrenia; however, the findings have not been consistent. This study aims to examine the association of AKT1 polymorphisms with drug-free and post-treatment symptomatology and social function in patients with schizophrenia. One hundred and twenty newly hospitalised patients with acutely exacerbated schizophrenia who had never been treated by atypical antipsychotics were recruited. They received optimal treatment of risperidone for up to 42 days in the inpatient research unit. Clinical manifestations were monitored by Positive and Negative Syndrome Scale (PANSS) and social function by Nurses' Observation Scale for Inpatients Evaluation (NOSIE). Patients were genotyped for eight AKT1 Single Nucleotide Polymorphism (SNPs), which have been previously investigated for association with schizophrenia. At drug-free status and after best possible treatment of risperidone, genotypes of each SNP did not influence performances in NOSIE, PANSS-total, -positive, -negative and -general psychopathology profiles. These results suggest that AKT1 does not play a significant role in clinical and functional manifestations in patients with schizophrenia who receive risperidone treatment. Future research should also focus on the relationships between genotypes of other susceptibility genes and phenotypes or functional outcomes of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 46 | Psychiatry Investig 2009 Jun 6: 102-7 |
| PMID | 20046382 |
| Title | AKT1 Gene Polymorphisms and Obstetric Complications in the Patients with Schizophrenia. |
| Abstract | We performed a genetic association study with schizophrenic patients to investigate whether the V-akt murine thymoma viral oncogene homolog 1 (AKT1) gene plays a role in obstetric complications. One-hundred-eighty patients with schizophrenia (male, 113; female, 67) were included. All patients fulfilled DSM-IV criteria for schizophrenia. Obstetric complications were measured by the Lewis scale. Prenatal and perinatal information was retrospectively collected from the patients' mothers. We selected six single nucleotide polymorphisms (SNPs) for the AKT1 gene: SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs 1130233), SNP5 (rs2494732), and SNPA (rs2498804). The genotype data were analyzed for an association with the Lewis total score in terms of allele, genotype, and haplotype distribution. The mean total Lewis scores were 1.30+/-1.61 for males and 1.54+/-1.87 for females. Higher total score tended to be correlated with an earlier age of onset of schizophrenia in females. In the total sample, no SNP was associated with obstetric complications. However, the additional analyses for male and female subgroups found a significant association between SNPA and SNP4 and Lewis score in females (p=0.02 for SNPA, p=0.04 for SNP4). The SNP5-SNPA haplotype showed a positive association with obstetric complications (p=0.03) in the female patient group. We found an association between SNPs in the AKT1 gene and total Lewis score measuring obstetric complications in female patients with schizophrenia. Because these findings did not survive a correction for multiple testing, the significance should be interpreted carefully and replication studies are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 47 | Acta Neuropsychiatr 2009 Jun 21: 109-20 |
| PMID | 26953749 |
| Title | Schizophrenia: genetics, prevention and rehabilitation. |
| Abstract | Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation. Medline search of relevant studies published between 1990 and 2008. In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism. This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 48 | Neurosci. Res. 2010 Mar 66: 238-45 |
| PMID | 19931325 |
| Title | No association between AKT1 polymorphism and schizophrenia: a case-control study in a Korean population and a meta-analysis. |
| Abstract | V-akt murine thymoma viral oncogene homolog 1 (AKT1) has been suggested to be involved in the pathophysiology of schizophrenia. Recent, independent studies in Caucasian, Japanese, Iranian, and Chinese populations have reported that the AKT1 gene may be associated with schizophrenia, but these results have yet to be replicated in other populations. In the present study, we performed a case-control association study between AKT1 and schizophrenia in a Korean population. We genotyped six single nucleotide polymorphisms (SNP1 (rs3803300), SNP2 (rs1130214), SNP3 (rs3730358), SNP4 (rs1130233), SNP5 (rs2494732), SNP A (rs2498804)) of AKT1, selected from previous reports, in a sample of 283 subjects with schizophrenia and 350 controls. No significant difference in single marker polymorphisms or haplotype frequencies of the six SNPs in the AKT1 gene was observed between controls and subjects with schizophrenia. In addition, we carried out an updated meta-analysis of the six SNPs, and found no evidence for an association between the six SNPs and schizophrenia. Taken together, our results do not support the hypothesis that AKT1 is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 49 | Arch. Gen. Psychiatry 2010 Oct 67: 991-1001 |
| PMID | 20921115 |
| Title | Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. |
| Abstract | NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. schizophrenia is a complex disorder, with etiology likely due to epistasis. To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling. Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 50 | PLoS ONE 2010 -1 5: e10789 |
| PMID | 20520724 |
| Title | Epistatic and functional interactions of catechol-o-methyltransferase (COMT) and AKT1 on neuregulin1-ErbB signaling in cell models. |
| Abstract | Neuregulin1 (NRG1)-ErbB signaling has been implicated in the pathogenesis of cancer and schizophrenia. We have previously reported that NRG1-stimulated migration of B lymphoblasts is PI3K-AKT1dependent and impaired in patients with schizophrenia and significantly linked to the catechol-o-methyltransferase (COMT) Val108/158Met functional polymorphism. We have now examined AKT1 activation in NRG1-stimulated B lymphoblasts and other cell models and explored a functional relationship between COMT and AKT1. NRG1-induced AKT1 phosphorylation was significantly diminished in Val carriers compared to Met carriers in both normal subjects and in patients. Further, there was a significant epistatic interaction between a putatively functional coding SNP in AKT1 (rs1130233) and COMT Val108/158Met genotype on AKT1 phosphorylation. NRG1 induced translocation of AKT1 to the plasma membrane also was impaired in Val carriers, while PIP(3) levels were not decreased. Interestingly, the level of COMT enzyme activity was inversely correlated with the cells' ability to synthesize phosphatidylserine (PS), a factor that attracts the pleckstrin homology domain (PHD) of AKT1 to the cell membrane. Transfection of SH-SY5Y cells with a COMT Val construct increased COMT activity and significantly decreased PS levels as well as NRG1-induced AKT1 phosphorylation and migration. Administration of S-adenosylmethionine (SAM) rescued all of these deficits. These data suggest that AKT1 function is influenced by COMT enzyme activity through competition with PS synthesis for SAM, which in turn dictates AKT1-dependent cellular responses to NRG1-mediated signaling. Our findings implicate genetic and functional interactions between COMT and AKT1 and may provide novel insights into pathogenesis of schizophrenia and other ErbB-associated human diseases such as cancer. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 51 | Psychiatr. Genet. 2010 Jun 20: 118-22 |
| PMID | 20421846 |
| Title | Genetic association of the AKT1 gene with schizophrenia in a British population. |
| Abstract | A number of studies have reported a genetic association of the AKT1 gene with schizophrenia, although some have failed to replicate the AKT1 association. This study was undertaken to further explore the AKT1 association with more single nucleotide polymorphisms in a British sample. A total of 221 families, consisting of 148 fathers, 204 mothers and 222 offspring affected with schizophrenia, were recruited for genetic analysis. Analysis for allelic and haplotypic associations was performed with the UNPHASED program, using likelihood-based association analysis for nuclear families with missing parental genotype data. Allelic association was detected at rs1130214 (chi(2)=6.28, P=0.012) and at rs11847866 (chi(2)=4.64, P=0.031), although the remaining single nucleotide polymorphisms did not show allelic association with schizophrenia. The global P value of overall associations was 0.059 after 10000 permutations. Assessment using the Haploview program revealed rs1130214, rs2494746 and rs11847866 in the same linkage disequilibrium block and haplotype analysis showed disease association for the rs1130214-rs2494746-rs11847866 haplotypes (chi(2)=10.18, d.f.=4, P=0.037), of which the T-G-A haplotype was excessively transmitted (chi(2)=6.93, uncorrected P=0.008) and this haplotypic association survived Bonferroni correction (P=0.04). The present results provide further evidence to support the AKT1 association with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 52 | Int. J. Neuropsychopharmacol. 2010 Sep 13: 981-96 |
| PMID | 20219156 |
| Title | Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency. |
| Abstract | Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 53 | Genes Brain Behav. 2010 Jul 9: 503-11 |
| PMID | 20214684 |
| Title | Association of AKT1 gene variants and protein expression in both schizophrenia and bipolar disorder. |
| Abstract | The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 54 | Neuropharmacology 2010 Feb 58: 452-6 |
| PMID | 19747927 |
| Title | Serotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients. |
| Abstract | Several investigations have reported associations the serotonin 1A (5-HT1A) receptor to schizophrenia and psychotic disorders, making 5-HT1A receptor gene (HTR1A) an adequate candidate gene for the pathophysiology of schizophrenia and methamphetamine (METH)-induced psychosis. Huang and colleagues reported that rs6295 in HTR1A was associated with schizophrenia. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. It may indicate that METH-induced psychosis and schizophrenia have common susceptibility genes. In support of this hypothesis, we reported that the V-act murine thymoma viral oncogene homologue 1 (AKT1) gene was associated with METH-induced psychosis and schizophrenia in the Japanese population. Furthermore, we conducted an analysis of the association of HTR1A with METH-induced psychosis. Using one functional SNP (rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Rs878567 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this significance remained after Bonferroni correction. In addition, we detected an association between rs6295 and rs878567 in HTR1A and METH-induced psychosis patients in the haplotype-wise analysis. Although we detected an association between rs6295 and METH-induced psychosis patients, this significance disappeared after Bonferroni correction. HTR1A may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. However, because we did not perform a mutation scan of HTR1A, a replication study using a larger sample may be required for conclusive results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 55 | Arch. Gen. Psychiatry 2010 Oct 67: 991-1001 |
| PMID | 20921115 |
| Title | Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. |
| Abstract | NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. schizophrenia is a complex disorder, with etiology likely due to epistasis. To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP. schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls. A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172). Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging. We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling. Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 56 | Neurosci. Lett. 2011 Aug 501: 41-4 |
| PMID | 21741444 |
| Title | Genetic studies of the protein kinase AKT1 in Parkinson's disease. |
| Abstract | The protein kinase AKT1 belongs to the Akt family and is a potent mediator of cell growth and survival and fully activated when phosphorylated. The AKT family has been found to be phosphorylated to a lesser extent in the dopaminergic cells of Parkinson's disease patients compared to control individuals, which might influence cell survival. Several publications support the implication of AKT1 in disorders of the dopaminergic system including bipolar disease and schizophrenia. In 2008 an association study performed in a Greek Parkinson's disease case-control material reported the identification of a protective AKT1 haplotype. Based on their work we have performed a replication study in a Swedish Parkinson's disease cohort. We genotyped the four single nucleotide polymorphims (SNPs): rs2494743, rs2498788, rs2494746 and rs1130214 in a case-control material consisting of 243 Parkinson patients and 315 controls. We did not find any associations with Parkinson's disease for either the individual SNPs or any of the haplotypes. In contrast to previously published results, our data do not support the hypothesis of genetic variants in AKT1 confering protection against Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 57 | Neurosci Biobehav Rev 2011 Jan 35: 848-70 |
| PMID | 20951727 |
| Title | Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. |
| Abstract | schizophrenia is a severe mental illness that afflicts nearly 1% of the world's population. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity. Although the etiology of schizophrenia is unknown, it appears to be a developmental disorder involving the interaction of a potentially large number of risk genes, with no one gene producing a strong effect except rare, highly penetrant copy number variants. The purpose of this review is to detail how putative schizophrenia risk genes (DISC-1, neuregulin/ErbB4, dysbindin, AKT1, BDNF, and the NMDA receptor) are involved in regulating neuroplasticity and how alterations in their expression may contribute to the disconnectivity observed in schizophrenia. Moreover, this review highlights how many of these risk genes converge to regulate common neurotransmitter systems and signaling pathways. Future studies aimed at elucidating the functions of these risk genes will provide new insights into the pathophysiology of schizophrenia and will likely lead to the nomination of novel therapeutic targets for restoring proper synaptic connectivity in the brain in schizophrenia and related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 58 | Neuropsychopharmacol Hung 2011 Dec 13: 205-10 |
| PMID | 22184188 |
| Title | Genetic predisposition to schizophrenia: what did we learn and what does the future hold? |
| Abstract | schizophrenia is a complex, devastating brain disorder with clear genetic and environmental contributions to the emergence of the disease. In the last several decades of research hundreds of millions of dollars were spent of the elusive search for schizophrenia susceptibility genes, but the results have been meager. Researchers have identified a number of genetic variants that predispose the brain to developing the disease, yet alone they can explain only a very small number of the schizophrenia occurrence. Vulnerability in DISC1, NRG1, DTNBP1, RGS4, KCNH2, COMT, AKT1 and other putative schizophrenia genes, together with copy number variants, leave unexplained the vast majority of diseased cases. Furthermore, most of the uncovered disease-associated genetic variants have been inconsistently replicated across multiple cohorts and do not lead to altered protein structure. In summary, we argue that large-scale genetic studies will not provide us with the answers we seek: we have to accept that there are no schizophrenia-predisposing genes with large effect sizes, and due to the diversity of findings, genetics-based novel therapies of schizophrenia are not realistic. The new treatments will have to come from functional studies of intracellular pathways and understanding the confluence of environmental influences and genetic predisposition, and their combined effects on developmental mechanisms and intracellular cascades. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 59 | Mol Autism 2011 -1 2: 9 |
| PMID | 21615902 |
| Title | Gene expression analysis in lymphoblasts derived from patients with autism spectrum disorder. |
| Abstract | The autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that result in severe and pervasive impairment in the development of reciprocal social interaction and verbal and nonverbal communication skills. In addition, individuals with ASD have stereotypical behavior, interests and activities. Rare mutations of some genes, such as neuroligin (NLGN) 3/4, neurexin (NRXN) 1, SHANK3, MeCP2 and NHE9, have been reported to be associated with ASD. In the present study, we investigated whether alterations in mRNA expression levels of these genes could be found in lymphoblastoid cell lines derived from patients with ASD. We measured mRNA expression levels of NLGN3/4, NRXN1, SHANK3, MeCP2, NHE9 and AKT1 in lymphoblastoid cells from 35 patients with ASD and 35 healthy controls, as well as from 45 patients with schizophrenia and 45 healthy controls, using real-time quantitative reverse transcriptase polymerase chain reaction assays. The mRNA expression levels of NLGN3 and SHANK3 normalized by ?-actin or TBP were significantly decreased in the individuals with ASD compared to controls, whereas no difference was found in the mRNA expression level of MeCP2, NHE9 or AKT1. However, normalized NLGN3 and SHANK3 gene expression levels were not altered in patients with schizophrenia, and expression levels of NLGN4 and NRXN1 mRNA were not quantitatively measurable in lymphoblastoid cells. Our results provide evidence that the NLGN3 and SHANK3 genes may be differentially expressed in lymphoblastoid cell lines from individuals with ASD compared to those from controls. These findings suggest the possibility that decreased mRNA expression levels of these genes might be involved in the pathophysiology of ASD in a substantial population of ASD patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 60 | Proc. Natl. Acad. Sci. U.S.A. 2011 Jan 108: 1158-63 |
| PMID | 21187413 |
| Title | DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. |
| Abstract | The D2/AKT1/GSK-3? signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3? proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3?, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 61 | Arch. Gen. Psychiatry 2011 Feb 68: 148-57 |
| PMID | 21041608 |
| Title | Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. |
| Abstract | Individual differences exist in sensitivity to the psychotomimetic effect of cannabis; the molecular genetic basis underlying differential sensitivity remains elusive. To investigate whether selected schizophrenia candidate single-nucleotide polymorphisms (SNPs) moderate effects of cannabis use. Interactions between recent cannabis use, determined by urinalysis results, and 152 SNPs in 42 candidate genes were examined in 740 unaffected siblings of 801 patients with psychosis to examine genetic moderation of the association between Structured Interview for schizotypy-Revised positive schizotypy and recent cannabis use (at-risk paradigm). The SNPs showing Bonferroni-adjusted association in the at-risk paradigm were used in a case-only analysis in the 801 patients, as well as in a case-sibling and case-control analysis (using 419 controls) focusing on genetic moderation of developmental effects of cannabis on later psychotic disorder. The Netherlands and Flanders, Belgium. Eight hundred one patients with psychosis and their 740 unaffected siblings. Significant interaction between any of the selected SNPs and cannabis in the at-risk paradigm, followed by selective case-only, case-sibling, and case-control analyses. In the unaffected siblings, 16 SNPs in 12 genes showed significant interaction at P < .05, 3 of which survived correction for multiple testing (P < .0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). Follow-up analysis supported AKT1 rs2494732 × cannabis interaction in the case-only (? = 0.20; P = .007), case-sibling (interaction P = .040), and case-control (interaction P = .057) analyses, with individuals with C/C genotypes having an approximately 2-fold odds of being diagnosed with a psychotic disorder when having used cannabis. In the unaffected siblings, the AKT1 × cannabis interaction explained 2.2% additional variance in schizotypy in the whole sample and 19.0% additional variance in the exposed siblings with recent cannabis use. Genetic variation in AKT1 may mediate both short-term as well as longer-term effects on psychosis expression associated with use of cannabis, possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D(2) receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 62 | Neuroscience 2011 Feb 174: 178-89 |
| PMID | 20888398 |
| Title | Behavioral phenotyping of v-akt murine thymoma viral oncogene homolog 1-deficient mice reveals a sex-specific prepulse inhibition deficit in females that can be partially alleviated by glycogen synthase kinase-3 inhibitors but not by antipsychotics. |
| Abstract | schizophrenia is a severe mental illness with a strong genetic predisposition. Accumulating evidence from human genetics and animal studies suggest v-akt murine thymoma viral oncogene homolog 1 (AKT1) might contribute to susceptibility for schizophrenia. In contrast to inconclusive findings in human genetic studies, a mutant mouse model is a simplified and alternative approach to determining the biological functions of AKT1 and its possible role in the pathogenesis of schizophrenia. In study 1, a comprehensive battery of behavioral tests was performed on both male and female mice. The results of behavioral phenotyping did not reveal significant differences between genotypes or sexes, except increased time of immobility in the tail suspension test and acoustic prepulse inhibition (PPI) deficits in AKT1-knockout females. On the basis of the observed PPI deficit, in study 2a, neuromorphological alterations were examined with morphometric analysis of green fluorescent protein (GFP)-labeled pyramidal neurons in the auditory cortex of female mice. The results indicated abnormalities in the architecture and complexity of the neurons of mutant females compared with those of the controls. In study 2b, potentially effective pharmacological treatments were explored to mitigate the observed PPI deficits in females. Antipsychotics (either raclopride (3 mg/kg) or clozapine (3 mg/kg)) did not alleviate observed PPI deficits in AKT1-knockout females but it was partially normalized by 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT, 5 mg/kg) and SB216763 (2.5 mg/kg). These findings imply the importance of AKT1 in some behavioral phenotypes and dendritic morphology in the auditory cortex of female mice, and they also suggest that subjects with AKT1 deficiency are insensitive to antipsychotic drugs, whereas glycogen synthase kinase-3 (GSK3) inhibitors could have therapeutic potential for the treatment of acoustic PPI deficits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 63 | Arch. Gen. Psychiatry 2011 Feb 68: 148-57 |
| PMID | 21041608 |
| Title | Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis: sibling analysis and proband follow-up. |
| Abstract | Individual differences exist in sensitivity to the psychotomimetic effect of cannabis; the molecular genetic basis underlying differential sensitivity remains elusive. To investigate whether selected schizophrenia candidate single-nucleotide polymorphisms (SNPs) moderate effects of cannabis use. Interactions between recent cannabis use, determined by urinalysis results, and 152 SNPs in 42 candidate genes were examined in 740 unaffected siblings of 801 patients with psychosis to examine genetic moderation of the association between Structured Interview for schizotypy-Revised positive schizotypy and recent cannabis use (at-risk paradigm). The SNPs showing Bonferroni-adjusted association in the at-risk paradigm were used in a case-only analysis in the 801 patients, as well as in a case-sibling and case-control analysis (using 419 controls) focusing on genetic moderation of developmental effects of cannabis on later psychotic disorder. The Netherlands and Flanders, Belgium. Eight hundred one patients with psychosis and their 740 unaffected siblings. Significant interaction between any of the selected SNPs and cannabis in the at-risk paradigm, followed by selective case-only, case-sibling, and case-control analyses. In the unaffected siblings, 16 SNPs in 12 genes showed significant interaction at P < .05, 3 of which survived correction for multiple testing (P < .0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). Follow-up analysis supported AKT1 rs2494732 × cannabis interaction in the case-only (? = 0.20; P = .007), case-sibling (interaction P = .040), and case-control (interaction P = .057) analyses, with individuals with C/C genotypes having an approximately 2-fold odds of being diagnosed with a psychotic disorder when having used cannabis. In the unaffected siblings, the AKT1 × cannabis interaction explained 2.2% additional variance in schizotypy in the whole sample and 19.0% additional variance in the exposed siblings with recent cannabis use. Genetic variation in AKT1 may mediate both short-term as well as longer-term effects on psychosis expression associated with use of cannabis, possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D(2) receptor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 64 | Curr. Pharm. Des. 2012 -1 18: 5024-35 |
| PMID | 22716151 |
| Title | Gene-environment interactions underlying the effect of cannabis in first episode psychosis. |
| Abstract | Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 65 | Mol. Psychiatry 2012 Oct 17: 1007-16 |
| PMID | 21788944 |
| Title | Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications. |
| Abstract | AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 66 | Brain 2012 May 135: 1436-45 |
| PMID | 22525159 |
| Title | Effective connectivity of AKT1-mediated dopaminergic working memory networks and pharmacogenetics of anti-dopaminergic treatment. |
| Abstract | Working memory is a limited capacity system that integrates and manipulates information across brief periods of time, engaging a network of prefrontal, parietal and subcortical brain regions. Genetic control of these heritable brain processes have been suggested by functional genetic variations influencing dopamine signalling, which affect prefrontal activity during complex working memory tasks. However, less is known about genetic control over component working memory cortical-subcortical networks in humans, and the pharmacogenetic implications of dopamine-related genes on cognition in patients receiving anti-dopaminergic drugs. Here, we examined predictions from basic models of dopaminergic signalling in cortical and cortical-subcortical circuitries implicated in dissociable working memory maintenance and manipulation processes. We also examined pharmacogenetic effects on cognition in the context of anti-dopaminergic drug therapy. Using dynamic causal models of functional magnetic resonance imaging in normal subjects (n?=?46), we identified differentiated effects of functional polymorphisms in COMT, DRD2 and AKT1 genes on prefrontal-parietal and prefrontal-striatal circuits engaged during maintenance and manipulation, respectively. Cortical synaptic dopamine monitored by the COMT Val158Met polymorphism influenced prefrontal control of both parietal processing in working memory maintenance and striatal processing in working memory manipulation. DRD2 and AKT1 polymorphisms implicated in DRD2 signalling influenced only the prefrontal-striatal network associated with manipulation. In the context of anti-psychotic drugs, the DRD2 and AKT1 polymorphisms altered dose-response effects of anti-psychotic drugs on cognition in schizophrenia (n?=?111). Thus, we suggest that genetic modulation of DRD2-AKT1-related prefrontal-subcortical circuits could at least in part influence cognitive dysfunction in psychosis and its treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 67 | Front Mol Neurosci 2012 -1 5: 33 |
| PMID | 22435049 |
| Title | AKT/GSK3 signaling pathway and schizophrenia. |
| Abstract | schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3? in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 68 | PLoS ONE 2012 -1 7: e32618 |
| PMID | 22393424 |
| Title | Marked reduction of AKT1 expression and deregulation of AKT1-associated pathways in peripheral blood mononuclear cells of schizophrenia patients. |
| Abstract | Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood Mononuclear Cells (PBMCs) of schizophrenia patients. To examine PBMC expression levels of AKT1 in schizophrenia patients versus controls, and to examine whether functional biological processes in which AKT1 plays an important role are deregulated in schizophrenia patients. A case-control study, investigating whole-genome PBMC gene expression in male, recent onset (<5 years) schizophrenia patients (N?=?41) as compared to controls (N?=?29). Genes, differentially expressed between patients and controls were identified using ANOVA with Benjamini-Hochberg correction (false discovery rate (FDR)?=?0.05). Functional aspects of the deregulated set of genes were investigated with the Ingenuity Pathway Analysis (IPA) Software Tool. We found significantly decreased PBMC expression of AKT1 (p<0.001, t?=?-4.25) in the patients. AKT1 expression was decreased in antipsychotic-free or -naive patients (N?=?11), in florid psychotic (N?=?20) and in remitted (N?=?21) patients. A total of 1224 genes were differentially expressed between patients and controls (FDR?=?0.05). Functional analysis of the entire deregulated gene set indicated deregulated canonical pathways involved in a large number of cellular processes: immune system, cell adhesion and neuronal guidance, neurotrophins and (neural) growth factors, oxidative stress and glucose metabolism, and apoptosis and cell-cycle regulation. Many of these processes are associated with AKT1. We show significantly decreased PBMC gene expression of AKT1 in male, recent-onset schizophrenia patients. Our observations suggest that decreased PBMC AKT1 expression is a stable trait in recent onset, male schizophrenia patients. We identified several AKT related cellular processes which are potentially affected in these patients, a majority of which play a prominent role in current schizophrenia hypotheses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 69 | Schizophr. Res. 2012 Mar 135: 8-14 |
| PMID | 22277669 |
| Title | Genetic overlap between schizophrenia and bipolar disorder: a study with AKT1 gene variants and clinical phenotypes. |
| Abstract | A number of epidemiological and genetic studies suggests an overlap of schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD). This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case-control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case-control studies of schizophrenia and schizoaffective disorder. Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p<0.001) and rs2498804 (p<0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects. AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 70 | J Psychiatr Res 2012 Mar 46: 279-84 |
| PMID | 22209534 |
| Title | Hippocampal volume and the AKT signaling system in first-episode schizophrenia. |
| Abstract | The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3? system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia. Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software. Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure. Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 71 | Hippocampus 2012 Feb 22: 230-40 |
| PMID | 21049487 |
| Title | Akt1 deficiency in schizophrenia and impairment of hippocampal plasticity and function. |
| Abstract | Genetic studies have associated deficient function of the serine/threonine kinase AKT1 with schizophrenia. This disorder is associated with developmental, structural, and functional abnormalities of the hippocampus that could be traced to abnormal AKT1 function. To establish a closer connection between AKT1 and hippocampal function, mice with a selective deletion of AKT1 (AKT1(-/-) mice) were examined for physiological and behavioral outcomes dependent on the hippocampus and associated with schizophrenia. Genetic deletion of AKT1 was associated with both impaired proliferative capacity of adult-born hippocampal progenitors and hippocampal long-term potentiation, indicating deficient functions of this brain region associated with neuroplasticity. Moreover, AKT1(-/-) mice demonstrated impairments in contextual fear conditioning and recall of spatial learning, behaviors known to selectively involve the hippocampus. AKT1(-/-) mice also showed reduced prepulse inhibition of the acoustic startle response, a sensorimotor gating response that is perturbed in schizophrenia. Postmortem tissue samples from patients with schizophrenia showed significant reductions of phosphorylated Akt levels in hilar neurons of the dentate gyrus, the neurogenic zone of the hippocampus. Taken together, these results implicate the AKT1 isoform in regulating hippocampal neuroplasticity and cognition and in contributing to the etiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 72 | Curr Neuropharmacol 2013 Sep 11: 535-58 |
| PMID | 24403877 |
| Title | Neurodevelopment in schizophrenia: the role of the wnt pathways. |
| Abstract | To review the role of Wnt pathways in the neurodevelopment of schizophrenia. SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are AKT1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 73 | Psychiatry Res 2013 Oct 209: 732-3 |
| PMID | 23747160 |
| Title | No association between AKT1 gene variants and schizophrenia: a Malaysian case-control study and meta-analysis. |
| Abstract | We aim to replicate AKT1 gene variants studies using Malaysian samples. Seven AKT1 single nucleotide polymorphisms (SNPs) were studied in 417 patients and 429 controls. Haplotype showed significant association (p=0.036) with schizophrenia, especially in Malays and Indians. Meta-analysis of rs2494732 showed significant association worldwide (p=0.018) and in Asians (p=0.023). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 74 | Cell. Mol. Life Sci. 2013 Mar 70: 935-50 |
| PMID | 23052218 |
| Title | Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling. |
| Abstract | The schizophrenia susceptibility gene, Rgs4, is one of the most intensively studied regulators of G-protein signaling members, well known to be fundamental in regulating neurotransmission. However, little is known about its role in the developing nervous system. We have isolated zebrafish rgs4 and shown that it is transcribed in the developing nervous system. Rgs4 knockdown did not affect neuron number and patterning but resulted in locomotion defects and aberrant development of axons. This was confirmed using a selective Rgs4 inhibitor, CCG-4986. Rgs4 knockdown also attenuated the level of phosphorylated-AKT1, and injection of constitutively-activated AKT1 rescued the motility defects and axonal phenotypes in the spinal cord but not in the hindbrain and trigeminal neurons. Our in vivo analysis reveals a novel role for Rgs4 in regulating axonogenesis during embryogenesis, which is mediated by another schizophrenia-associated gene, AKT1, in a region-specific manner. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 75 | Schizophr. Res. 2013 Jun 147: 14-23 |
| PMID | 23583326 |
| Title | Paliperidone protects prefrontal cortical neurons from damages caused by MK-801 via Akt1/GSK3? signaling pathway. |
| Abstract | Recent studies have suggested that neurodegeneration is involved in the pathogenesis of schizophrenia, and some atypical antipsychotics appear to prevent or retard progressive morphological brain changes. However, the underlying molecular mechanisms are largely unknown. Whether changes in intracellular signaling pathways are related to their neuroprotective effects remains undefined. In the present study, we used mouse embryonic prefrontal cortical neurons to examine the neuroprotection of paliperidone against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. Paliperidone inhibited MK-801 induced neurotoxicity both in MTT metabolism assay (p<0.01) and in lactate dehydrogenase (LDH) activity assay (p<0.01). Time course studies revealed that paliperidone effectively attenuated the elevation of intracellular free calcium concentration ([Ca(2+)]i) induced by exposure to MK-801 (p<0.01). Moreover, paliperidone could significantly retard MK-801-mediated inhibition of neurite outgrowth (p<0.01) and reverse MK-801-induced decreases of gene expression and phosphorylation of AKT1 and GSK3? (both p<0.01). Furthermore, these protective effects of paliperidone were blocked by pretreatment with a PI3K inhibitor LY294002. Taking together, our results demonstrated that paliperidone could protect prefrontal cortical neurons from MK-801-induced damages via AKT1/GSK3? signaling pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 76 | Int. J. Neuropsychopharmacol. 2013 Aug 16: 1483-503 |
| PMID | 23442539 |
| Title | Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication. |
| Abstract | Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 77 | Psychopharmacology (Berl.) 2013 Jun 227: 639-49 |
| PMID | 23392353 |
| Title | Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression. |
| Abstract | A number of studies have associated reduced AKT1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the AKT1 gene (AKT1(+/-)) show reduced AKT1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown. Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced AKT1 expression as a vulnerability factor for schizophrenia. Methods AKT1(+/-), AKT1(-/-), and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. AKT1(+/-) and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection. AKT1(+/-) and AKT1(-/-) mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. AKT1(+/-) mice displayed reduced pre-pulse inhibition. Reduced genetic expression of AKT1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced AKT1 expression can serve as a vulnerability factor for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 78 | World J. Biol. Psychiatry 2013 Mar 14: 100-13 |
| PMID | 22150081 |
| Title | The AKT1 gene is associated with attention and brain morphology in schizophrenia. |
| Abstract | A meta-analysis of the associations between genetic variants in the AKT1 gene and schizophrenia found that a single nucleotide polymorphism (SNP5; rs2494732) was associated with schizophrenia in Asian populations. In this study, we investigated the effects of this SNP on memory and attentional performance and brain structure using magnetic resonance imaging in a Japanese population (117 patients with schizophrenia and 189 healthy subjects). The memory performance, particularly attention/concentration score, measured by the Wechsler Memory Scale-Revised in A carriers of SNP5, which was found to be enriched in patients with schizophrenia, was lower than that in individuals with the G/G genotype. We confirmed the association of the SNP with attentional performance using the Continuous Performance Test, which assessed sustained attention and vigilance of attentional function. Patients with A allele demonstrated lower attentional performance than patients with the G/G genotype. Patients with the A allele had smaller gray matter volumes in the right inferior parietal lobule related to attentional processes and in the frontostriatal region related to different SNPs in AKT1 than patients with the G/G genotype. Our results suggest that a genetic variant of AKT1 might be associated with attentional deficits and brain morphological vulnerability in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 79 | Am. J. Med. Genet. A 2013 Dec 161A: 2931-7 |
| PMID | 24039187 |
| Title | The AKT genes and their roles in various disorders. |
| Abstract | AKT (AK mouse plus Transforming or Thymoma) is a common oncogene expressed in most tissues. Both AKT2 and AKT3, although important, have more limited distributions. The regulation of all three genes depends on two receptors-a receptor tyrosine kinase with a growth factor ligand, and a G protein coupled receptor, also with a ligand together with an explanation of how their downsteam components function. AKT2 is amplified or overexpressed in cancer with a higher frequency than those found with AKT1. AKT1 is cardioprotective to the heart by supporting its physiological growth and function. AKT2 is closely linked to Type II diabetes and the implications of various types of mutations are discussed. Various AKT3 mutations are important in neurological disorders, such as microcephaly, hemimegalencephaly, and megalencephaly syndromes. Finally, a reduced level of AKT1 in the frontal cortex has been found during post-mortem brain studies of schizophrenic patients in the populations of many countries. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 80 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 81 | Front Behav Neurosci 2014 -1 8: 455 |
| PMID | 25688191 |
| Title | Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. |
| Abstract | Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of AKT1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male AKT1 (+/-), Nrg1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between AKT1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of AKT1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 82 | Schizophr. Res. 2014 Aug 157: 120-7 |
| PMID | 24962437 |
| Title | Paliperidone protects SK-N-SH cells against glutamate toxicity via Akt1/GSK3? signaling pathway. |
| Abstract | schizophrenia is a heterogeneous psychotic illness and its etiology remains poorly understood. Recent studies have suggested that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics appear to slow progressive morphological brain changes. In addition, the atypical antipsychotics were reported to have a superior therapeutic efficacy in treating schizophrenia and have a low incidence of extrapyramidal side effects (EPS) compared to typical antipsychotics. However, the mechanisms of atypical antipsychotics in treating schizophrenia and the basis for differences in their clinical effects were still totally unknown. In the present study, we investigated whether paliperidone shows protective effects on SK-N-SH cells from cell toxicity induced by exposure to glutamate. We examined the effects of the drugs on cell viability (measured by MTT metabolism assay and lactate dehydrogenase (LDH) activity assay), apoptosis rate, ROS levels and gene expression and phosphorylation of AKT1 and GSK3?. The results showed that paliperidone significantly increases the cell viability by MTT and LDH assays (p<0.05), in contrast to the typical antipsychotic (haloperidol), which had little neuroprotective activity. Moreover, paliperidone retarded the glutamate-mediated promotion of ROS and the rate of apoptosis (p<0.05). In addition, paliperidone also effectively reversed glutamate-induced decreases of gene expression and phosphorylation of AKT1 and GSK3? (both p<0.05). Our results demonstrated that paliperidone could effectively protect SK-N-SH cells from glutamate-induced damages via AKT1/GSK3? signaling pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 83 | Front Psychiatry 2014 -1 5: 54 |
| PMID | 24904437 |
| Title | Gone to Pot - A Review of the Association between Cannabis and Psychosis. |
| Abstract | Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 84 | Front Psychiatry 2014 -1 5: 48 |
| PMID | 24860514 |
| Title | Gene-environment interactions in severe mental illness. |
| Abstract | Severe mental illness (SMI) is a broad category that includes schizophrenia, bipolar disorder, and severe depression. Both genetic disposition and environmental exposures play important roles in the development of SMI. Multiple lines of evidence suggest that the roles of genetic and environmental factors depend on each other. Gene-environment interactions may underlie the paradox of strong environmental factors for highly heritable disorders, the low estimates of shared environmental influences in twin studies of SMI, and the heritability gap between twin and molecular heritability estimates. Sons and daughters of parents with SMI are more vulnerable to the effects of prenatal and postnatal environmental exposures, suggesting that the expression of genetic liability depends on environment. In the last decade, gene-environment interactions involving specific molecular variants in candidate genes have been identified. Replicated findings include an interaction between a polymorphism in the AKT1 gene and cannabis use in the development of psychosis and an interaction between the length polymorphism of the serotonin transporter gene and childhood maltreatment in the development of persistent depressive disorder. Bipolar disorder has been underinvestigated, with only a single study showing an interaction between a functional polymorphism in the BDNF gene and stressful life events triggering bipolar depressive episodes. The first systematic search for gene-environment interactions has found that a polymorphism in CTNNA3 may sensitize the developing brain to the pathogenic effect of cytomegalovirus in utero, leading to schizophrenia in adulthood. Strategies for genome-wide investigations will likely include coordination between epidemiological and genetic research efforts, systematic assessment of multiple environmental factors in large samples, and prioritization of genetic variants. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 85 | Neuroscience 2014 Mar 263: 257-68 |
| PMID | 24444829 |
| Title | Soft-diet feeding after weaning affects behavior in mice: Potential increase in vulnerability to mental disorders. |
| Abstract | Mastication is one of the most important oral functions, and the period during which mastication is acquired overlaps with the term of rapid development and maturation of the neural systems. In particular, the acquisition period after weaning is related to the potential onset of mental disorders. However, the roles of mastication during this period for brain development remain largely unknown. Therefore, we used a series of standard behavioral analyses, assessment of hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF), TrkB, and AKT1 in the hippocampus and frontal cortex of mice to investigate the effects of post-weaning mastication on brain function. We fed 21-day-old C57BL6/J male mice either a hard or a soft diet for 4weeks and conducted a series of standard behavioral tests from 7weeks of age. Further, histological analysis with bromodeoxyuridine was performed to compare hippocampal cell proliferation at 7 and 14weeks of age. Real-time polymerase chain reaction was performed to compare BDNF, TrkB, and AKT1 expression in the hippocampus and frontal cortex of 14-week-old mice. Compared to mice fed a hard diet (HDM), soft-diet mice (SDM) showed behavioral impairments, including decreased home cage activity, increased open field test activity, and deficits in prepulse inhibition. These results were similar to those observed in mouse models of schizophrenia. However, no effects were observed on anxiety-like behaviors or memory/learning tests. Compared to HDM, SDM showed significantly decreased hippocampal cell proliferation and hippocampal BDNF and AKT1 gene expression at 14weeks of age. A soft diet after weaning may have resulted in histological and molecular changes in the hippocampus and influenced outcomes of behavioral tests related to mental disorders. Our findings suggest that soft-diet feeding after weaning may affect both physical and mental development of mice, and may increase vulnerability to mental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 86 | Transl Psychiatry 2014 -1 4: e339 |
| PMID | 24399042 |
| Title | Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. |
| Abstract | Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1, AKT1, DTNBP1, DNMT1, PPP3CC and SOX10, which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27,000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls (P=1.74 × 10(-4)). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 87 | J Psychiatr Res 2014 Jan 48: 94-101 |
| PMID | 24128664 |
| Title | Increased susceptibility to apoptosis in cultured fibroblasts from antipsychotic-naïve first-episode schizophrenia patients. |
| Abstract | Altered apoptosis has been proposed as a potential mechanism involved in the abnormal neurodevelopment and neurodegenerative processes associated with schizophrenia. The aim of this study was to investigate in primary fibroblast cultures whether antipsychotic-naïve patients with first-episode schizophrenia have greater apoptotic susceptibility than healthy controls. Cell growth, cell viability and various apoptotic hallmarks (caspase-3 activity, translocation of phosphatidylserine, chromatin condensation and gene expression of AKT1, BAX, BCL2, CASP3, GSK3B and P53) were measured in fibroblast cultures obtained from skin biopsies of patients (n = 11) and healthy controls (n = 8), both in basal conditions and after inducing apoptosis with staurosporine. Compared to controls, cultured fibroblasts from patients showed higher caspase-3 activity and lower BCL2 expression. When exposed to staurosporine, fibroblasts from patients also showed higher caspase-3 activity; a higher percentage of cells with translocated phosphatidylserine and condensed chromatin; and higher p53 expression compared to fibroblasts from controls. No differences in cell viability or cell growth were detected. These results strongly support the hypothesis that first-episode schizophrenia patients may have increased susceptibility to apoptosis, which may be involved in the onset and progression of the disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 88 | Schizophr Bull 2014 Mar 40: 388-98 |
| PMID | 23474853 |
| Title | A sex- and region-specific role of Akt1 in the modulation of methamphetamine-induced hyperlocomotion and striatal neuronal activity: implications in schizophrenia and methamphetamine-induced psychosis. |
| Abstract | AKT1 (also known as protein kinase B, ?), a serine/threonine kinase of AKT family, has been implicated in both schizophrenia and methamphetamine (Meth) use disorders. AKT1 or its protein also has epistatic effects on the regulation of dopamine-dependent behaviors or drug effects, especially in the striatum. The aim of this study is to investigate the sex-specific role of AKT1 in the regulation of Meth-induced behavioral sensitization and the alterations of striatal neurons using AKT1(-/-) mice and wild-type littermates as a model. A series of 4 Experiments were conducted. Meth-induced hyperlocomotion and Meth-related alterations of brain activity were measured. The neural properties of striatal medium spiny neurons (MSNs) were also characterized. Further, 17?-estradiol was applied to examine its protective effect in Meth-sensitized male mice. Our findings indicate that (1) AKT1(-/-) males were less sensitive to Meth-induced hyperlocomotion during Meth challenge compared with wild-type controls and AKT1(-/-) females, (2) further sex differences were revealed by coinjection of Meth with raclopride but not SCH23390 in Meth-sensitized AKT1(-/-) males, (3) Meth-induced alterations of striatal activity were confirmed in AKT1(-/-) males using microPET scan with (18)F-flurodeoxyglucose, (4) AKT1 deficiency had a significant impact on the electrophysiological and neuromorphological properties of striatal MSNs in male mice, and (5) subchronic injections of 17?-estradiol prevented the reduction of Meth-induced hyperactivity in Meth-sensitized AKT1(-/-) male mice. This study highlights a sex- and region-specific effect of AKT1 in the regulation of dopamine-dependent behaviors and implies the importance of AKT1 in the modulation of sex differences in Meth sensitivity and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 89 | Front Behav Neurosci 2014 -1 8: 455 |
| PMID | 25688191 |
| Title | Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia. |
| Abstract | Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of AKT1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male AKT1 (+/-), Nrg1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between AKT1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of AKT1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 90 | Front Psychiatry 2014 -1 5: 54 |
| PMID | 24904437 |
| Title | Gone to Pot - A Review of the Association between Cannabis and Psychosis. |
| Abstract | Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 91 | Mol. Neurobiol. 2015 Oct -1: -1 |
| PMID | 26491028 |
| Title | Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis. |
| Abstract | In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-?) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine?×?treatment?×?gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 92 | Biol. Direct 2015 -1 10: 59 |
| PMID | 26450699 |
| Title | MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1]. |
| Abstract | While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 93 | CNS Neurol Disord Drug Targets 2015 -1 14: 1086-95 |
| PMID | 25801838 |
| Title | Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco. |
| Abstract | schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 94 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Jan 56: 149-54 |
| PMID | 25194460 |
| Title | Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats. |
| Abstract | Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 95 | Biol. Direct 2015 -1 10: 59 |
| PMID | 26450699 |
| Title | MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1]. |
| Abstract | While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 96 | Biol. Direct 2015 -1 10: 59 |
| PMID | 26450699 |
| Title | MicroRNA-derived network analysis of differentially methylated genes in schizophrenia, implicating GABA receptor B1 [GABBR1] and protein kinase B [AKT1]. |
| Abstract | While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 97 | CNS Neurol Disord Drug Targets 2015 -1 14: 1086-95 |
| PMID | 25801838 |
| Title | Association of Single Nucleotide Polymorphisms in Catechol-O-Methyltransferase and Serine-Threonine Protein Kinase Genes in the Pakistani Schizophrenic Population: A Study with Special Emphasis on Cannabis and Smokeless Tobacco. |
| Abstract | schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population. Polymerase chain reactionrestriction fragment length polymorphism (PCR-RFLP) and DNA sequencing were used to identify SNPs in the genes. The present study shows that COMT Val and COMT Met allelic frequencies for the controls were p=0.52, q=0.48 and for the schizophrenic cases they were p=0.34, q=0.66 respectively. The distribution of polymorphism in COMT Val158Met genotype by Hardy-Weinberg equilibrium (HWE) was P=0.61 for controls and P=0.005 for cases. The data reveal that SNP rs1130214 T allele mutation was found neither in patients nor in controls in the 5' untranslated region (UTR). This proves that no association of AKT1 and positive association of COMT with schizophrenia exist in the population of Pakistan. Moreover, a study based on a single family showed COMT Met allele inheritance in schizophrenic offspring. This suggested that COMT allele alteration influences susceptibility to at least some forms of psychosis in the Pakistani population. Interestingly, according to our socio-economical survey, COMT genotype has no association with cannabis but it is strongly associated with tobacco. The Pakistani population with Val158Met SNP showed more susceptibility towards developing schizophrenia. This study highlights the genetic differences between Pakistani and other Caucasian populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 98 | Neuropharmacology 2016 May 108: 403-414 |
| PMID | 27163190 |
| Title | Disruption of Akt signaling decreases dopamine sensitivity in modulation of inhibitory synaptic transmission in rat prefrontal cortex. |
| Abstract | Akt is a serine/threonine kinase, which is dramatically reduced in the prefrontal cortex (PFC) of patients with schizophrenia, and a deficiency in AKT1 results in PFC function abnormalities. Although the importance of Akt in dopamine (DA) transmission is well established, how impaired Akt signaling affects the DA modulation of synaptic transmission in the PFC has not been characterized. Here we show that Akt inhibitors significantly decreased receptor sensitivity to DA by shifting DA modulation of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in prefrontal cortical neurons. Akt inhibition caused a significant decrease in synaptic dopamine D2 receptor (D2R) levels with high-dose DA exposure. In addition, Akt inhibition failed to affect DA modulation of IPSCs after blockade of ?-arrestin 2. ?-arrestin 2-mediated interaction of clathrin with D2R was enhanced by co-application of a Akt inhibitor and DA. Taken together, the reduced response in DA modulation of inhibitory transmission mainly involved ?-arrestin 2-dependent D2R desensitization. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 99 | Mol. Neurobiol. 2016 May -1: -1 |
| PMID | 27173157 |
| Title | The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway. |
| Abstract | schizophrenia is one of the most severe psychiatric disorders. Increasing evidence implicates that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics are neuroprotective and successful in slowing the progressive morphological brain changes. As an antipsychotic agent, clozapine has superior and unique effects, but the intracellular signaling pathways that mediate clozapine action remain to be elucidated. The phosphatidylinositol-3-kinase/protein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is crucial for neuronal survival. However, little information is available regarding this pathway with clozapine. In the present study, we investigated the protective effect of clozapine on the PC12 cells against corticosterone toxicity. Our results showed that corticosterone decreases the phosphorylation of Akt and FoxO3a, leading to the nuclear localization of FoxO3a and the apoptosis of PC12 cells, while clozapine concentration dependently protected PC12 cells against corticosterone insult. Pathway inhibitors studies displayed that the protective effect of clozapine was reversed by LY294002 and wortmannin, two PI3K inhibitors, or Akt inhibitor VIII although several other inhibitors had no effect. The shRNA knockdown results displayed that downregulated AKT1 or FoxO3a attenuated the protective effect of clozapine. Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone. Together, our data indicates that clozapine protects PC12 cells against corticosterone-induced cell death by modulating activity of the PI3K/Akt/FoxO3a pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 100 | Metab Brain Dis 2016 Apr -1: -1 |
| PMID | 27041387 |
| Title | The known and missing links between Toxoplasma gondii and schizophrenia. |
| Abstract | Toxoplasma gondii, an intracellular protozoan parasite, has a striking predilection for infecting the Central Nervous System and has been linked to an increased incidence of a number of psychiatric diseases. Several in vitro and in vivo studies have shown that T. gondii infection can affect the structure, bioenergetics and function of brain cells, and alters several host cell processes, including dopaminergic, tryptophan-kynurenine, GABAergic, AKT1, Jak/STAT, and vasopressinergic pathways. These mechanisms underlying the neuropathology of latent toxoplasmosis seem to operate also in schizophrenia, supporting the link between the two disorders. Better understanding of the intricate parasite-neuroglial communications holds the key to unlocking the mystery of T. gondii-mediated schizophrenia and offers substantial prospects for the development of disease-modifying therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 101 | Biol. Psychiatry 2016 Apr 79: 526-38 |
| PMID | 26970363 |
| Title | Human Laboratory Studies on Cannabinoids and Psychosis. |
| Abstract | Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 102 | Sci Rep 2016 -1 6: 16767 |
| PMID | 26733343 |
| Title | Altered expression of mRNA profiles in blood of early-onset schizophrenia. |
| Abstract | To identify gene expression abnormalities in schizophrenia (SZ), we generated whole-genome gene expression profiles using microarrays on peripheral blood mononuclear cells (PBMCs) from 18 early-onset SZ cases and 12 controls. We detected 84 transcripts differentially expressed by diagnostic status, with 82 genes being upregulated and 2 downregulated. We identified two SZ associated gene coexpression modules (green and red), including 446 genes . The green module is positively correlated with SZ, encompassing predominantly up-regulated genes in SZ; while the red module was negatively correlated with disease status, involving mostly nominally down-regulated genes in SZ. The olfactory transduction pathway was the most enriched pathways for the genes within the two modules. The expression levels of several hub genes, including AKT1, BRCA1, CCDC134, UBD, and ZIC2 were validated using real-time quantitative PCR. Our findings indicate that mRNA coexpression abnormalities may serve as a promising mechanism underlying the development of SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |
| 103 | Transl Psychiatry 2016 -1 6: e738 |
| PMID | 26882038 |
| Title | AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. |
| Abstract | Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis-which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content-and also ± 7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy, schizotypal |