1Am. J. Med. Genet. 2000 Dec 96: 716-20
PMID11121167
TitleMutation and association analysis of the Fyn kinase gene with alcoholism and schizophrenia.
AbstractLack of FYN tyrosine kinase increases alcohol sensitivity. FYN phosphorylates a component of the NMDA receptor, which may be involved in schizophrenia. The FYN gene is located on human chromosome 6q21, to which linkage of schizophrenia has been suggested. We hypothesized that the FYN gene is a candidate for predisposition to alcoholism and schizophrenia, and we performed a mutation study of the 5'-flanking region, all coding exons, and exon-intron junctions of the FYN gene. The SSCP mutation analysis was performed in 48 unrelated alcoholics and 16 unrelated schizophrenics. Three polymorphisms, -93A/G in the 5'-flanking region, IVS10+37T/C in intron 10, and Ex12+894T/G in the 3'-untranslated region, were identified. A rare variant of Ex12+1162TG in the 3'-untranslated region was also detected. Neither missense nor nonsense mutations were found. Case-control studies using a larger sample of unrelated patients and controls did not reveal significant associations between these polymorphisms and alcoholism or schizophrenia. In addition, genotyping a microsatellite marker, D6S302, located in intron 10 of the FYN gene, did not show a significant association between the marker and alcoholism or schizophrenia. Results of the present study did not provide evidence for the involvement of the genomic FYN gene mutations in alcoholism or schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:716-720, 2000.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2Am. J. Med. Genet. 2000 Dec 96: 716-20
PMID11121167
TitleMutation and association analysis of the Fyn kinase gene with alcoholism and schizophrenia.
AbstractLack of FYN tyrosine kinase increases alcohol sensitivity. FYN phosphorylates a component of the NMDA receptor, which may be involved in schizophrenia. The FYN gene is located on human chromosome 6q21, to which linkage of schizophrenia has been suggested. We hypothesized that the FYN gene is a candidate for predisposition to alcoholism and schizophrenia, and we performed a mutation study of the 5'-flanking region, all coding exons, and exon-intron junctions of the FYN gene. The SSCP mutation analysis was performed in 48 unrelated alcoholics and 16 unrelated schizophrenics. Three polymorphisms, -93A/G in the 5'-flanking region, IVS10+37T/C in intron 10, and Ex12+894T/G in the 3'-untranslated region, were identified. A rare variant of Ex12+1162TG in the 3'-untranslated region was also detected. Neither missense nor nonsense mutations were found. Case-control studies using a larger sample of unrelated patients and controls did not reveal significant associations between these polymorphisms and alcoholism or schizophrenia. In addition, genotyping a microsatellite marker, D6S302, located in intron 10 of the FYN gene, did not show a significant association between the marker and alcoholism or schizophrenia. Results of the present study did not provide evidence for the involvement of the genomic FYN gene mutations in alcoholism or schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:716-720, 2000.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3Brain Res. Mol. Brain Res. 2003 Apr 112: 90-4
PMID12670706
TitleExpression of Fyn, a non-receptor tyrosine kinase in prefrontal cortex from patients with schizophrenia and its correlation with clinical onset.
AbstractFYN is a member of the non-receptor tyrosine kinase family, which is known to be closely involved in signal transduction in neurons and has an important role in the development and organisation of the central nervous system. In order to explore the possible role of FYN in schizophrenia, the expression of FYN messenger RNA (mRNA) and protein were investigated in the postmortem prefrontal cortex of brains from normal and 'schizophrenic' cases. There was an increase in both total area FYN mRNA signal (17.7%, P<0.05) and cellular mRNA content (15.7%, P<0.05) in the schizophrenic group relative to controls. In parallel the content of FYN protein detected by immuno-autoradiography was also increased in the schizophrenic cases (21.8% P<0.05). In addition, the cellular FYN mRNA signal was negatively correlated with the age of onset (r=-0.94, P=0.0026). These results suggest that an increase in FYN expression may contribute to the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4Brain Res. Mol. Brain Res. 2003 Apr 112: 90-4
PMID12670706
TitleExpression of Fyn, a non-receptor tyrosine kinase in prefrontal cortex from patients with schizophrenia and its correlation with clinical onset.
AbstractFYN is a member of the non-receptor tyrosine kinase family, which is known to be closely involved in signal transduction in neurons and has an important role in the development and organisation of the central nervous system. In order to explore the possible role of FYN in schizophrenia, the expression of FYN messenger RNA (mRNA) and protein were investigated in the postmortem prefrontal cortex of brains from normal and 'schizophrenic' cases. There was an increase in both total area FYN mRNA signal (17.7%, P<0.05) and cellular mRNA content (15.7%, P<0.05) in the schizophrenic group relative to controls. In parallel the content of FYN protein detected by immuno-autoradiography was also increased in the schizophrenic cases (21.8% P<0.05). In addition, the cellular FYN mRNA signal was negatively correlated with the age of onset (r=-0.94, P=0.0026). These results suggest that an increase in FYN expression may contribute to the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5Neurosci. Lett. 2003 May 343: 70-2
PMID12750000
TitleNo genetic association between polymorphisms in the Fyn kinase gene and age of schizophrenic onset.
AbstractSince the mRNA level of FYN, a neurodevelopmental molecule, expression had been reported to be increased in postmortem schizophrenic prefrontal cortex and showed a strong correlation with age of disease onset, we investigated whether the three polymorphisms of the FYN gene on genomic DNA (-93A/G, IVS10+37T/C and Ex12+894T/G) also had an effect on clinical onset in 139 unrelated schizophrenics. A comparison of the age of onset among the groups classified by polymorphisms showed no significant difference. Moreover, all allelic combinations also failed to show significant differences in age of onset among the groups. The present study reports that there is no indication that the three polymorphisms in the FYN gene are associated with the age of schizophrenic onset.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6Neurosci. Lett. 2003 May 343: 70-2
PMID12750000
TitleNo genetic association between polymorphisms in the Fyn kinase gene and age of schizophrenic onset.
AbstractSince the mRNA level of FYN, a neurodevelopmental molecule, expression had been reported to be increased in postmortem schizophrenic prefrontal cortex and showed a strong correlation with age of disease onset, we investigated whether the three polymorphisms of the FYN gene on genomic DNA (-93A/G, IVS10+37T/C and Ex12+894T/G) also had an effect on clinical onset in 139 unrelated schizophrenics. A comparison of the age of onset among the groups classified by polymorphisms showed no significant difference. Moreover, all allelic combinations also failed to show significant differences in age of onset among the groups. The present study reports that there is no indication that the three polymorphisms in the FYN gene are associated with the age of schizophrenic onset.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7No To Shinkei 2004 Feb 56: 153-6
PMID15098360
Title[Analysis of the fyn kinase gene in Alzheimer's disease and schizophrenia].
AbstractReelin is a protein which plays an important role in cell construction and proliferation of neurons during the development of the central nervous system. Several lines of evidence suggest a possible role for reelin-related genes in the etiology of neurodevelopmental as well as neurodegenerative diseases. It is possible that variations in reelin-related genes (Reelin, VLDLR, FYN, CNRs, a3b1INTEGRIN, mDAB1) may be involved in the pathogenesis of schizophrenia and Alzheimer's disease. We have been conducting a systematic survey of the association of reelin-related gene polymorphisms with these disorders. Previously, we examined the association of the triplet repeats of the reelin and VLDLR gene with schizophrenia. We found no significant association of schizophrenia with the trinucleotide repeat polymorphism of the reelin nor VLDLR genes (Akahane et al. 2002). In this study, we performed an allelic association analysis in Alzheimer's disease and schizophrenia with three polymorphisms of the FYN gene reported by Ishiguro et al (2000). Diagnosis was based on DSM-IV and NINCDS-ADRDA. We found no significant differences in genotype distribution or allelic frequency between patient and control groups. Thus, it is unlikely that these polymorphisms play an important role in the pathogenesis of Alzheimer's disease or schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8J. Neurosci. 2007 Apr 27: 4519-29
PMID17460065
TitleNeuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/- knock-outs compared with wild-type mice.
AbstractWe previously identified Neuregulin1 (NRG1) as a gene contributing to the risk of developing schizophrenia. Furthermore, we showed that NRG1+/- mutant mice display behavioral abnormalities that are reversed by clozapine, an atypical antipsychotic drug used for the treatment of schizophrenia. We now present evidence that ErbB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4), the tyrosine kinase receptor for NRG1 in hippocampal neurons, interacts with two nonreceptor tyrosine kinases, FYN and Pyk2 (proline-rich tyrosine kinase 2). NRG1 stimulation of cells expressing ErbB4 and FYN leads to the association of FYN with ErbB4 and consequent activation. Furthermore, we show that NRG1 signaling, through activation of FYN and Pyk2 kinases, stimulates phosphorylation of Y1472 on the NR2B subunit of the NMDA receptor (NMDAR), a key regulatory site that modulates channel properties. NR2B Y1472 is hypophosphorylated in NRG1+/- mutant mice, and this defect can be reversed by clozapine at a dose that reverses their behavioral abnormalities. We also demonstrate that short-term synaptic plasticity is altered and theta-burst long-term potentiation is impaired in NRG1+/- mutant mice, and incubation of hippocampal slices from these mice with NRG1 reversed those effects. Attenuated NRG1 signaling through ErbB4 may contribute to the pathophysiology of schizophrenia through dysfunction of NMDAR modulation. Thus, our data support the glutamate hypothesis of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9Psychiatr. Genet. 2007 Jun 17: 201-4
PMID17417065
TitlePolymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia.
AbstractThe glutamatergic system has been implicated in the pathogenesis and prefrontal cortex dysfunctions in schizophrenia. The Src-family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate, in prefrontal cortex. We estimated an association between three polymorphisms of FYN gene and performance on the Wisconsin Card Sorting Test, measuring prefrontal cortex functions, in 188 schizophrenic patients. Patients with T/T genotype of IVS10+T/C polymorphism and T/T genotype of Ex12+894T/G polymorphism made significantly less perseverative errors in the Wisconsin Card Sorting Test compared with patients with remaining genotypes, and obtained numerically better results in other Wisconsin Card Sorting Test domains. No significant differences in Wisconsin Card Sorting Test performance were found as to -93 A/G polymorphism. The main finding of the study is showing a relationship between polymorphisms of the FYN gene, related to the function of glutamatergic system, and a performance on neuropsychological test of prefrontal cortex activity in schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Psychiatr. Genet. 2007 Jun 17: 201-4
PMID17417065
TitlePolymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia.
AbstractThe glutamatergic system has been implicated in the pathogenesis and prefrontal cortex dysfunctions in schizophrenia. The Src-family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate, in prefrontal cortex. We estimated an association between three polymorphisms of FYN gene and performance on the Wisconsin Card Sorting Test, measuring prefrontal cortex functions, in 188 schizophrenic patients. Patients with T/T genotype of IVS10+T/C polymorphism and T/T genotype of Ex12+894T/G polymorphism made significantly less perseverative errors in the Wisconsin Card Sorting Test compared with patients with remaining genotypes, and obtained numerically better results in other Wisconsin Card Sorting Test domains. No significant differences in Wisconsin Card Sorting Test performance were found as to -93 A/G polymorphism. The main finding of the study is showing a relationship between polymorphisms of the FYN gene, related to the function of glutamatergic system, and a performance on neuropsychological test of prefrontal cortex activity in schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
11Schizophr Bull 2009 Nov 35: 1163-82
PMID18552348
TitleSchizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.
AbstractMany genes implicated in schizophrenia can be related to glutamatergic transmission and neuroplasticity, oligodendrocyte function, and other families clearly related to neurobiology and schizophrenia phenotypes. Others appear rather to be involved in the life cycles of the pathogens implicated in the disease. For example, aspartylglucosaminidase (AGA), PLA2, SIAT8B, GALNT7, or B3GAT1 metabolize chemical ligands to which the influenza virus, herpes simplex, cytomegalovirus (CMV), rubella, or Toxoplasma gondii bind. The epidermal growth factor receptor (EGR/EGFR) is used by the CMV to gain entry to cells, and a CMV gene codes for an interleukin (IL-10) mimic that binds the host cognate receptor, IL10R. The fibroblast growth factor receptor (FGFR1) is used by herpes simplex. KPNA3 and RANBP5 control the nuclear import of the influenza virus. Disrupted in schizophrenia 1 (DISC1) controls the microtubule network that is used by viruses as a route to the nucleus, while DTNBP1, MUTED, and BLOC1S3 regulate endosomal to lysosomal routing that is also important in viral traffic. Neuregulin 1 activates ERBB receptors releasing a factor, EBP1, known to inhibit the influenza virus transcriptase. Other viral or bacterial components bind to genes or proteins encoded by CALR, FEZ1, FYN, HSPA1B, IL2, HTR2A, KPNA3, MED12, MED15, MICB, NQO2, PAX6, PIK3C3, RANBP5, or TP53, while the cerebral infectivity of the herpes simplex virus is modified by Apolipoprotein E (APOE). Genes encoding for proteins related to the innate immune response, including cytokine related (CCR5, CSF2RA, CSF2RB, IL1B, IL1RN, IL2, IL3, IL3RA, IL4, IL10, IL10RA, IL18RAP, lymphotoxin-alpha, tumor necrosis factor alpha [TNF]), human leukocyte antigen (HLA) antigens (HLA-A10, HLA-B, HLA-DRB1), and genes involved in antigen processing (angiotensin-converting enzyme and tripeptidyl peptidase 2) are all concerned with defense against invading pathogens. Human microRNAs (Hsa-mir-198 and Hsa-mir-206) are predicted to bind to influenza, rubella, or poliovirus genes. Certain genes associated with schizophrenia, including those also concerned with neurophysiology, are intimately related to the life cycles of the pathogens implicated in the disease. Several genes may affect pathogen virulence, while the pathogens in turn may affect genes and processes relevant to the neurophysiology of schizophrenia. For such genes, the strength of association in genetic studies is likely to be conditioned by the presence of the pathogen, which varies in different populations at different times, a factor that may explain the heterogeneity that plagues such studies. This scenario also suggests that drugs or vaccines designed to eliminate the pathogens that so clearly interact with schizophrenia susceptibility genes could have a dramatic effect on the incidence of the disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Psychiatry Res 2009 Jul 168: 119-28
PMID19501919
TitleDecreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia.
AbstractFYN, a Src-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, FYN participates in brain development, synaptic transmission through the phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that FYN is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether FYN abnormalities are present in patients with schizophrenia, we analyzed FYN expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of FYN protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of FYN were altered in the patients and their relatives; specifically, the ratio of FYNDelta7, in which exon 7 is absent, was elevated. An expression study in HEK293T cells revealed that FYNDelta7 had a dominant-negative effect on the phosphorylation of FYN's substrate. These results suggest novel deficits in FYN function, manifested as the downregulation of FYN protein or the altered transcription of the FYN gene, in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Neuropsychobiology 2009 -1 59: 178-83
PMID19468241
TitleFYN kinase gene: another glutamatergic gene associated with bipolar disorder?
AbstractSeveral genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (-93A/G in the 5'-flanking region), rs6916861 (Ex12+894T/G in the 3'-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with -93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r(2) = 0.86, D' = 0.93 with 95% CI = 0.9-0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14Neuropsychobiology 2009 -1 59: 178-83
PMID19468241
TitleFYN kinase gene: another glutamatergic gene associated with bipolar disorder?
AbstractSeveral genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The Src family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (-93A/G in the 5'-flanking region), rs6916861 (Ex12+894T/G in the 3'-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with -93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r(2) = 0.86, D' = 0.93 with 95% CI = 0.9-0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15J. Neurochem. 2009 Jul 110: 631-40
PMID19457089
TitleEffects of the antipsychotic drug haloperidol on the somastostatinergic system in SH-SY5Y neuroblastoma cells.
AbstractAntipsychotics are established drugs in schizophrenia treatment which, however, are not free of side effects. Lipid rafts are critical for normal brain function. Several G protein-coupled receptors, such as somatostatin (SRIF) receptors, have been shown to localize to lipid rafts. The aim of this study was to investigate whether haloperidol treatment affects the composition and functionality of lipid rafts in SH-SY5Y neuroblastoma cells. Haloperidol inhibited cholesterol biosynthesis, leading to a marked reduction in cell cholesterol content and to an accumulation of sterol intermediates, particularly cholesta-8,14-dien-3beta-ol. These changes were accompanied by a loss of flotillin-1 and FYN from the lipid rafts. We next studied the functionality of the SRIF receptor. Treatment with haloperidol reduced the inhibitory effect of SRIF on adenylyl cyclase (AC) activity. On the other side, haloperidol decreased basal AC activity but increased forskolin-stimulated AC activity. Addition of free cholesterol to the culture medium abrogated the effects of haloperidol on lipid raft composition and SRIF signaling whereas the AC response to forskolin remained elevated. The results show that haloperidol, by affecting cholesterol homeostasis, ultimately alters SRIF signaling and AC activity, which might have physiological consequences.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
16Mol Brain 2010 -1 3: 20
PMID20569495
TitleDopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons.
AbstractInteractions between dopamine and glutamate in the prefrontal cortex are essential for cognitive functions such as working memory. Modulation of N-methyl-D-aspartic acid (NMDA) receptor functions by dopamine D1 receptor is believed to play a critical role in these functions. The aim of the work reported here is to explore the signaling pathway underlying D1 receptor-mediated trafficking of NMDA receptors in cultured rat prefrontal cortical neurons.
Activation of D1 receptor by selective agonist SKF-81297 significantly increased the expression of NR2B subunits. This effect was completely blocked by small interfering RNA knockdown of FYN, but not Src. Under control conditions, neither FYN nor Src knockdown exhibited significant effect on basal NR2B expression. D1 stimulation significantly enhanced NR2B insertion into plasma membrane in cultured PFC neurons, a process obstructed by FYN, but not Src, knockdown.
Dopamine D1 receptor-mediated increase of NMDA receptors is thus FYN kinase dependent. Targeting this signaling pathway may be useful in treating drug addiction and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
17Neuropsychopharmacology 2012 Mar 37: 896-905
PMID22048463
TitleAbnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia.
AbstractRecent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3'-5'-cyclic adenosine monophosphate (cAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and cAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and cAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, FYN, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and cAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and cAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
18Yale J Biol Med 2012 Dec 85: 481-90
PMID23239949
TitleA common STEP in the synaptic pathology of diverse neuropsychiatric disorders.
AbstractSynaptic function is critical for proper cognition, and synaptopathologies have been implicated in diverse neuropsychiatric disorders. STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-enriched tyrosine phosphatase that normally opposes synaptic strengthening by dephosphorylating key neuronal signaling molecules. STEP targets include N-methyl D-aspartate receptors (NMDARs) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), as well as extracellular signal-regulated kinase (ERK) and the tyrosine kinase FYN. STEP-mediated dephosphorylation promotes the internalization of NMDARs and AMPARs and the inactivation of ERK and FYN.Regulation of STEP is complex, and recent work has implicated STEP dysregulation in the pathophysiology of several neuropsychiatric disorders. Both high levels and low levels of STEP are found in a diverse group of illnesses. This review focuses on the role of STEP in three disorders in which STEP levels are elevated: Alzheimer's disease, fragile X syndrome, and schizophrenia. The presence of elevated STEP in all three of these disorders raises the intriguing possibility that cognitive deficits resulting from diverse etiologies may share a common molecular pathway.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
19Pharmacol. Rev. 2012 Jan 64: 65-87
PMID22090472
TitleTherapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders.
AbstractStriatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase FYN, N-methyl-D-aspartate receptors (NMDARs), and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and FYN leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
20Psychiatr. Genet. 2013 Feb 23: 39-40
PMID23250004
TitleAssociation study of the Fyn gene with schizophrenia in the Chinese-Han population.
Abstract-1
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
21Genes Brain Behav. 2014 Sep 13: 643-52
PMID25103464
TitleBehavioral characterization of striatal-enriched protein tyrosine phosphatase (STEP) knockout mice.
AbstractStriatal-enriched protein tyrosine phosphatase (STEP) has been described as a regulator of multiple kinases and glutamate receptor subunits critical for synaptic plasticity. Published behavioral and biochemical characterization from the founder line of STEP knockout (KO) mice revealed superior cognitive performance, with enhanced phosphorylation of substrates such as ERK, FYN and GluN2B; suggesting that inhibitors of STEP may have potential as therapeutic agents for the treatment of neuropsychiatric disorders. The objectives of this work aimed to replicate and extend the previously reported behavioral consequences of STEP knockout. Consistent with previous reported data, STEP KO mice demonstrated exploratory activity levels and similar motor coordination relative to WT littermate controls as well as intact memory in a Y-maze spatial novelty test. Interestingly, KO mice demonstrated deficits in pre-pulse inhibition as well as reduced seizure threshold relative to WT controls. Immunohistochemical staining of brains revealed the expected gene-dependent reduction in STEP protein confirming knockout in the mice. The present data confirm expression and localization of STEP and the absence in KO mice, and describe functional downstream implications of reducing STEP levels in vivo.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
22Front Cell Neurosci 2014 Jan 7: 284
PMID24431989
TitleAxon-glia interaction and membrane traffic in myelin formation.
AbstractIn vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasizing the central role of the Src-family kinase FYN during central nervous system (CNS) myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of proteolipid protein (PLP) transport by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
23Neuroscience 2014 Oct 278: 62-9
PMID25130559
TitleDownstream effects of striatal-enriched protein tyrosine phosphatase reduction on RNA expression in vivo and in vitro.
AbstractStriatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific tyrosine phosphatase that has been shown to de-phosphorylate several key neuronal signaling proteins, including kinases (extracellular signal-regulated kinase (ERK1/2), FYN, PYK2) and glutamate receptor subunits (N-methyl-d-aspartate receptor subtype 2B (NR2B), glutamate receptor 2 (GLUR2)). Step knock-out mice have increased phosphorylation of these substrates in the brain, with potential functional consequences in synaptic plasticity and cognitive tasks. It is therefore of interest to identify the molecular pathways and downstream transcriptional targets that are impacted by Step knockdown. In the present study, striatal RNA samples from Step wild-type, knock-out and heterozygous mice were hybridized to Affymetrix microarray chips and evaluated for transcriptional changes between genotypes. Pathway analysis highlighted Erk signaling and multiple pathways related to neurotrophin signaling, neuronal development and synaptic transmission. Potential genes of interest identified by microarray were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) in the cortex and hippocampus, which shared several transcriptional alterations with the striatum. In order to evaluate Step knockdown in an in vitro system, a panel of genes were evaluated using qRT-PCR in rat cortical neurons that were transduced with lentivirus expressing short hairpin RNA against Step or a non-targeting control. Our data suggest that Step has a role in the expression of immediate early genes relevant to synaptic plasticity, in both in vitro and in vivo systems.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
24Curr. Pharm. Des. 2015 -1 21: 3739-59
PMID26044973
Title5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.
Abstract5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and FYN-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
25Mol. Psychiatry 2015 Jul 20: 827-38
PMID25155877
TitleGlutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients.
Abstractschizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of FYN kinase activity, reversed by either the antioxidant N-acetylcysteine or FYN kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of FYN mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
26Acta Physiol (Oxf) 2016 Jan 216: 42-89
PMID25728499
TitleDopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.
AbstractDopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, FYN, NF-?B, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, schizophrenia and Tourette), patient's T cells seem to have abnormal DRs expression and/or responses to dopamine or production of dopamine, (xiii) drugs that affect the dopaminergic system have potent effects on T cells (e.g. dopamine=Intropin, L-dopa, bromocriptine, haloperidol, quinpirole, reserpine, pergolide, ecopipam, pimozide, amantadine, tetrabenazine, nomifensine, butaclamol). Dopamine-induced activation of resting Teffs and suppression of Tregs seem beneficial for health and may also be used for immunotherapy of cancer and infectious diseases. Independently, suppression of DRs in autoimmune and pro-inflammatory T cells, and also in cancerous T cells, may be advantageous. The review is relevant to Immunologists, Neurologists, Neuroimmunologists, Hematologists, Psychiatrists, Psychologists and Pharmacologists.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
27J Neurodev Disord 2016 -1 8: 14
PMID27134685
TitleEffects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.
AbstractNeurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch.
Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA.
Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p?FYN (p?=?0.055) relative to females. In contrast, effects of DTNBP1 were evident exclusively in the hippocampus. The developmental trajectory of GluN2B was disrupted in DTNBP1 null mice (genotype??age interaction p?FYN (only in females; p?Sex and DTNBP1 mutation influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, FYN, and PLC?. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics