| 1 | J Adv Nurs 2001 Sep 35: 812-8 |
|---|---|
| PMID | 11555028 |
| Title | Characteristics of an Accident and Emergency liaison mental health service in East London. |
| Abstract | To analyse the work of a liaison mental health service at the Accident and Emergency (A & E) department of a hospital in East London. The English National Service Frameworks (NSF) for Mental Health recommend that A & E departments provide liaison mental health services and this study reports how a service in East London is responding to this challenge. Data were collected during a 14-month period using a specially designed audit form. The typical referral was aged 36, of either sex, United Kingdom (UK) non-White with a diagnosis of depression. The majority of referrals were in the afternoon and seen immediately. A slight majority were known to mental health services; many were new referrals. Older and male clients were more likely, and Bengali and other Asian clients were less likely, to be registered with a psychiatrist. There were seasonal variations in referral type. Emergency referrals tended to have a diagnosis of schizophrenia; urgent and non-urgent referrals were more likely to be depressed. The outcome for the majority of referrals was referral to appropriate community services. The majority of non-clinical referrals were for advice, information and support. The service seems a useful resource for A & E staff, and clients with mental health problems. The service is a channel through which people access mental health services and appears to address the NSF for Mental Health. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Neurosci. Lett. 2001 Jun 305: 185-8 |
| PMID | 11403936 |
| Title | A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients. |
| Abstract | The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neurosci. Lett. 2001 Jun 305: 185-8 |
| PMID | 11403936 |
| Title | A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients. |
| Abstract | The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J. Psychopharmacol. (Oxford) 2003 Dec 17: 7-10 |
| PMID | 14964625 |
| Title | Bipolar disorder ignored by the Mental Health National Service framework but not forgotten by the British Association for Psychopharmacology. |
| Abstract | Bipolar disorder (BD) is a severe mental illness that has been largely ignored by the National Service Framework (NSF) for Mental Health. This is particularly notable because it is associated with a higher suicide rate than schizophrenia and has a greater burden of disability. The NSF offers little guidance on service models that specifically consider BD. This is of concern because of the complexities that are inherent in the management of BD. These deficiencies in the NSF may have far-reaching implications for resource allocation, service organization, and patient management and well-being. Moreover, the standards and performance targets laid out in the NSF will be difficult to meet if this important and common mental illness is not specifically catered for in mental health services. Local Implementation Teams would be well advised to take note of the recently published British Association for Psychopharmacology guidelines for the management of BD. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Schizophr. Res. 2003 Sep 63: 27-38 |
| PMID | 12892855 |
| Title | Sensitivity and specificity of select biological indices in characterizing psychotic patients and their relatives. |
| Abstract | Although studies have detailed biological abnormalities in schizophrenia patients and their first-degree biological relatives, few studies have directly compared the utility of biological indices in these individuals. Measures of global smooth-pursuit ocular motor (OM) function, low frequency and alpha band electroencephalogram (EEG) power, and nonspecific fluctuations (NSF) in electrodermal activity and visibility of the plexus in the nailfold were collected from 136 schizophrenia patients and 67 of their first-degree biological relatives, 71 affective disorder psychotic patients and 68 of their first-degree biological relatives, and 169 nonpsychiatric comparison subjects. We conducted receiver operator characteristic (ROC) analyses to determine how well each index differentiated the patient groups and the groups of first-degree relatives. Smooth-pursuit ocular motor function, low frequency and alpha band EEG power, and nailfold plexus visibility differentiated schizophrenia patients from nonpsychiatric comparison subjects. Nailfold plexus visibility was the only measure that significantly differentiated schizophrenia patients from both nonpsychiatric controls and affective patients. Smooth-pursuit ocular motor function and the number of electrodermal nonspecific fluctuations differentiated relatives of schizophrenia patients from nonpsychiatric comparison subjects. Increased nailfold plexus visibility may mark a process associated with abnormal brain development leading to schizophrenia. Smooth-pursuit dysfunction may mark genetic vulnerability that is relatively specific to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Brain Res. Bull. 2004 Mar 63: 45-55 |
| PMID | 15121238 |
| Title | Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington's disease mutation. |
| Abstract | Changes in mRNA expression of soluble NSF-attachment protein receptors (SNAREs) and SNARE-associated proteins have been shown to occur in a number of disorders such as schizophrenia, Alzheimer's disease and Parkinson's disease. We have shown previously that there is a decrease in protein levels of the SNARE-associated protein, complexin II (CPLXII) in Huntington's disease brain and in the R6/2 mouse model of Huntington's disease. In the current study, we used quantitative in situ hybridisation to examine mRNA expression of SNAREs (25 kDa synaptosome-associated protein (SNAP-25), syntaxin-1A and synaptobrevin-2) and SNARE-associated proteins (alpha-SNAP, CPLXI and CPLXII) in brain of R6/2 mice and their wild type littermates between 3 and 15 weeks of age. We found an early and progressive decrease of CPLXII expression in R6/2 mice brains. In contrast, no changes in SNARE expression were seen in R6/2 brains compared with wild type brain. Further, while decreased expression of alpha-SNAP and CPLXI was seen, this was not until 15 weeks of age and even then the changes were small. We suggest that downregulation of expression of mRNA encoding SNARE-associated proteins, first CPLXII and later CPLXI and alpha-SNAP, contributes to the progressive neuropathology of the R6/2 mouse model of Huntington's disease. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Neurosci. Lett. 2006 Jan 391: 112-5 |
| PMID | 16165270 |
| Title | N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder. |
| Abstract | N-Ethylmaleimide sensitive factor (NSF) is a presynaptic protein that has been suggested to be differentially expressed in the cortex of schizophrenic subjects through both high-throughput proteomic and genomic screening studies. Thus, to expand upon these studies we measured NSF using Western blotting in four regions of the cortex (BA9, 10, 40 and 46), in a cohort comprising 20 schizophrenic subjects, 8 bipolar I disorder subjects, and 20 control subjects. There was no significant difference in NSF levels between diagnostic cohorts in any of the four cortical regions. These findings highlight the importance of validating findings from high-throughput screening studies and do not support changes in cortical NSF as being of significance in schizophrenia or bipolar 1 disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Neurosci. Lett. 2006 Jan 391: 112-5 |
| PMID | 16165270 |
| Title | N-Ethylmaleimide sensitive factor in the cortex of subjects with schizophrenia and bipolar I disorder. |
| Abstract | N-Ethylmaleimide sensitive factor (NSF) is a presynaptic protein that has been suggested to be differentially expressed in the cortex of schizophrenic subjects through both high-throughput proteomic and genomic screening studies. Thus, to expand upon these studies we measured NSF using Western blotting in four regions of the cortex (BA9, 10, 40 and 46), in a cohort comprising 20 schizophrenic subjects, 8 bipolar I disorder subjects, and 20 control subjects. There was no significant difference in NSF levels between diagnostic cohorts in any of the four cortical regions. These findings highlight the importance of validating findings from high-throughput screening studies and do not support changes in cortical NSF as being of significance in schizophrenia or bipolar 1 disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Proc. Natl. Acad. Sci. U.S.A. 2007 Dec 104: 19942-7 |
| PMID | 18077426 |
| Title | Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. |
| Abstract | Evolutionarily significant selective sweeps may result in long stretches of homozygous polymorphisms in individuals from outbred populations. We developed whole-genome homozygosity association (WGHA) methodology to characterize this phenomenon in healthy individuals and to use this genomic feature to identify genetic risk loci for schizophrenia (SCZ). Applying WGHA to 178 SCZ cases and 144 healthy controls genotyped at 500,000 markers, we found that runs of homozygosity (ROHs), ranging in size from 200 kb to 15 mb, were common in unrelated Caucasians. Properties of common ROHs in healthy subjects, including chromosomal location and presence of nonancestral haplotypes, converged with prior reports identifying regions under selective pressure. This interpretation was further supported by analysis of multiethnic HapMap samples genotyped with the same markers. ROHs were significantly more common in SCZ cases, and a set of nine ROHs significantly differentiated cases from controls. Four of these 9 "risk ROHs" contained or neighbored genes associated with SCZ (NOS1AP, ATF2, NSF, and PIK3C3). Several of these risk ROHs were very rare in healthy subjects, suggesting that recessive effects of relatively high penetrance may explain a proportion of the genetic liability for SCZ. Other risk ROHs feature haplotypes that are also common in healthy individuals, possibly indicating a source of balancing selection. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Eur Arch Psychiatry Clin Neurosci 2008 Sep 258: 335-44 |
| PMID | 18347838 |
| Title | Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. |
| Abstract | The synaptosomal-associated protein of 25 kDa (SNAP-25) is part of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE), which mediates synaptic neurotransmission. In earlier studies a possible involvement of this protein in schizophrenia has been shown. As neurocognitive impairment is a core feature in the pathology of schizophrenia and considered to be a putative endophenotype according to genetic studies we investigated the influences of different SNAP-25 polymorphisms on neuropsychological test results before and during treatment with atypical antipsychotics. A total of 104 schizophrenic patients treated with atypical antipsychotics were genotyped for three different polymorphisms of the SNAP-25 gene (MnlI, TaiI and DdeI in the 3'-UTR). Cognitive function was assessed at baseline, week 4 or 6 and week 8 or 12. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. The MnlI and TaiI polymorphisms showed no associations to deficits on neuropsychological test results. In contrast, we observed a significant relation between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions. Homozygote T/T allele carriers of the DdeI polymorphism showed significant better neuropsychological test results in cognitive domains verbal memory and executive functions than those with the combined T/C and C/C genotypes (P < 0.01) at all three time points, but no differences in response to treatment with atypical antipsychotics. Additionally, TT carriers exhibited significantly better results in a general cognitive index (P < 0.05). As we observed an association between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions of schizophrenic patients our finding suggests that the SNAP-25 gene could play a role in the pathophysiology of neurocognitive dysfunctions in schizophrenia but is not predictive for treatment response with atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Eur Arch Psychiatry Clin Neurosci 2008 Sep 258: 335-44 |
| PMID | 18347838 |
| Title | Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. |
| Abstract | The synaptosomal-associated protein of 25 kDa (SNAP-25) is part of the soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment receptor (SNARE), which mediates synaptic neurotransmission. In earlier studies a possible involvement of this protein in schizophrenia has been shown. As neurocognitive impairment is a core feature in the pathology of schizophrenia and considered to be a putative endophenotype according to genetic studies we investigated the influences of different SNAP-25 polymorphisms on neuropsychological test results before and during treatment with atypical antipsychotics. A total of 104 schizophrenic patients treated with atypical antipsychotics were genotyped for three different polymorphisms of the SNAP-25 gene (MnlI, TaiI and DdeI in the 3'-UTR). Cognitive function was assessed at baseline, week 4 or 6 and week 8 or 12. Results of individual neuropsychological tests were assigned to six cognitive domains (reaction time and quality; executive function; working, verbal and visual memory) and a general cognitive index. The MnlI and TaiI polymorphisms showed no associations to deficits on neuropsychological test results. In contrast, we observed a significant relation between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions. Homozygote T/T allele carriers of the DdeI polymorphism showed significant better neuropsychological test results in cognitive domains verbal memory and executive functions than those with the combined T/C and C/C genotypes (P < 0.01) at all three time points, but no differences in response to treatment with atypical antipsychotics. Additionally, TT carriers exhibited significantly better results in a general cognitive index (P < 0.05). As we observed an association between the DdeI polymorphism of the SNAP-25 gene and cognitive dysfunctions of schizophrenic patients our finding suggests that the SNAP-25 gene could play a role in the pathophysiology of neurocognitive dysfunctions in schizophrenia but is not predictive for treatment response with atypical antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Psychiatr. Genet. 2009 Aug 19: 165-70 |
| PMID | 19451863 |
| Title | No evidence for excess runs of homozygosity in bipolar disorder. |
| Abstract | Recent studies have reported large common regions of homozygosity (ROHs) that are the result of autozygosity, that is, the cooccurrence within individuals of long haplotypes that have a high frequency in the population. A recent study reports that such regions are found more commonly in individuals with schizophrenia compared with controls, and identified nine 'risk ROHs' that were individually more common in cases. Of these, four contained or neighboured genes associated with schizophrenia (NOS1AP/UHMK1, ATF2, NSF and PIK3C3). We have applied the same methodology to a UK sample of 506 cases with bipolar disorder and 510 controls. There was no overall excess of common ROHs among bipolar individuals. With one exception, the haplotypes accounting for the ROHs appeared to be distributed according to the Hardy-Weinberg equilibrium. One ROH was individually more common among cases (uncorrected P = 0.0003). This ROH spanned the chromosome 2p23.3 gene ITSN2 (the gene for intersectin 2 isoform 2). However, inspection of the homozygous haplotypes and haplotype-based tests for association failed to provide a clearer understanding of why this ROH was occurring more commonly. Overall, we conclude that, in contrast with schizophrenia, common ROHs are rarely associated with susceptibility to bipolar disorder. This supports the idea that predominantly different genes are increasing susceptibility to schizophrenia and bipolar affective disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Neuroscience 2010 Apr 167: 135-42 |
| PMID | 20138128 |
| Title | Loss of synaptotagmin IV results in a reduction in synaptic vesicles and a distortion of the Golgi structure in cultured hippocampal neurons. |
| Abstract | Fusion of synaptic vesicles with the plasma membrane is mediated by the SNARE (soluble NSF attachment receptor) proteins and is regulated by synaptotagmin (syt). There are at least 17 syt isoforms that have the potential to act as modulators of membrane fusion events. Synaptotagmin IV (syt IV) is particularly interesting; it is an immediate early gene that is regulated by seizures and certain classes of drugs, and, in humans, syt IV maps to a region of chromosome 18 associated with schizophrenia and bipolar disease. Syt IV has recently been found to localize to dense core vesicles in hippocampal neurons, where it regulates neurotrophin release. Here we have examined the ultrastructure of cultured hippocampal neurons from wild-type and syt IV -/- mice using electron tomography. Perhaps surprisingly, we observed a potential synaptic vesicle transport defect in syt IV -/- neurons, with the accumulation of large numbers of small clear vesicles (putative axonal transport vesicles) near the trans-Golgi network. We also found an interaction between syt IV and KIF1A, a kinesin known to be involved in vesicle trafficking to the synapse. Finally, we found that syt IV -/- synapses exhibited reduced numbers of synaptic vesicles and a twofold reduction in the proportion of docked vesicles compared to wild-type. The proportion of docked vesicles in syt IV -/- boutons was further reduced, 5-fold, following depolarization. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Neuropsychopharmacology 2010 Sep 35: 2110-9 |
| PMID | 20571483 |
| Title | Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia. |
| Abstract | Several lines of evidence point to alterations of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor trafficking in schizophrenia. Multiple proteins, including synapse-associated protein 97 (SAP97), glutamate receptor-interacting protein 1 (GRIP1), and N-ethylmaleimide sensitive factor (NSF), facilitate the forward trafficking of AMPA receptors toward the synapse. Once localized to the synapse, AMPA receptors are trafficked in a complex endosomal system. We hypothesized that alterations in the expression of these proteins and alterations in the subcellular localization of AMPA receptors in endosomes may contribute to the pathophysiology of schizophrenia. Accordingly, we measured protein expression of SAP97, GRIP1, and NSF in the dorsolateral prefrontal cortex and found an increase in the expression of SAP97 and GRIP1 in schizophrenia. To determine the subcellular localization of AMPA receptor subunits, we developed a technique to isolate early endosomes from post-mortem tissue. We found increased GluR1 receptor subunit protein in early endosomes in subjects with schizophrenia. Together, these data suggest that there is an alteration of forward trafficking of AMPA receptors as well as changes in the subcellular localization of an AMPA receptor subunit in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | J. Neurochem. 2010 May 113: 601-14 |
| PMID | 20096092 |
| Title | Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat. |
| Abstract | The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, NSF, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Exp. Eye Res. 2013 Nov 116: 1-8 |
| PMID | 23954924 |
| Title | Developmental expression of dysbindin in Muller cells of rat retina. |
| Abstract | Dysbindin, the product of the DTNBP1 gene, was identified by yeast two hybrid assay as a binding partner of dystrobrevin, a cytosolic component of the dystrophin protein complex. Although its functional role has not yet been completely elucidated, the finding that dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1) suggests that it participates in intracellular trafficking and biogenesis of organelles and vesicles. Dysbindin is ubiquitous and in brain is expressed primarily in neurons. Variations at the dysbindin gene have been associated with increased risk for schizophrenia. As anomalies in retinal function have been reported in patients suffering from neuropsychiatric disorders, we investigated the expression of dysbindin in the retina. Our results show that differentially regulated dysbindin isoforms are expressed in rat retina during postnatal maturation. Interestingly, we found that dysbindin is mainly localized in Müller cells. The identification of dysbindin in glial cells may open new perspectives for a better understanding of the functional involvement of this protein in visual alterations associated to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Cereb. Cortex 2014 Feb 24: 364-76 |
| PMID | 23064108 |
| Title | Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs. |
| Abstract | Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Nat. Neurosci. 2015 Jul 18: 1008-16 |
| PMID | 26005852 |
| Title | The schizophrenia risk gene product miR-137 alters presynaptic plasticity. |
| Abstract | Noncoding variants in the human MIR137 gene locus increase schizophrenia risk with genome-wide significance. However, the functional consequence of these risk alleles is unknown. Here we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms in MIR137. We observed increased MIR137 levels compared to those in major allele-carrying cells. microRNA-137 gain of function caused downregulation of the presynaptic target genes complexin-1 (Cplx1), NSF and synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain of function resulted in changes in synaptic vesicle pool distribution, impaired induction of mossy fiber long-term potentiation and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | J. Proteome Res. 2015 Jan 14: 411-21 |
| PMID | 25363195 |
| Title | A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain. |
| Abstract | There is substantial interest in the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine in psychiatric research because it exerts acute psychotomimetic and rapid antidepressant effects in rodents and humans. Here, we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of interleukin 4, tumor necrosis factor alpha, and fibroblast growth factor 9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This involved changes in signaling kinases and proteases such as protein kinase C beta, neurochondrin (NCDN), calcineurin, extracellular signal-regulated kinsase 1 (ERK1), and mammalian target of rapamycin (MTOR). Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (mitochondrial aspartate aminotraNSFerase, catechol O-methyl traNSFerase, synaptic vesicle endo-/exocytosis (vesicle fusing ATPase (NSF), synapsin 1 (SYN1), syndapin-1 (PACN1)). Consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I, prohibitin (PHB) and neurofilament proteins (neurofilament light chain and ?-internexin (AINX)). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamine's mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | J. Neurosci. 2015 May 35: 7643-53 |
| PMID | 25972187 |
| Title | The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity. |
| Abstract | Dysbindin is a schizophrenia susceptibility factor and subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) required for lysosome-related organelle biogenesis, and in neurons, synaptic vesicle assembly, neurotransmission, and plasticity. Protein networks, or interactomes, downstream of dysbindin/BLOC-1 remain partially explored despite their potential to illuminate neurodevelopmental disorder mechanisms. Here, we conducted a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. We identified components of the vesicle fusion machinery as factors downregulated in dysbindin/BLOC-1 deficiency in neuroectodermal cells and iPSC-derived human neurons, among them the N-ethylmaleimide-sensitive factor (NSF). Human dysbindin/BLOC-1 coprecipitates with NSF and vice versa, and both proteins colocalized in a Drosophila model synapse. To test the hypothesis that NSF and dysbindin/BLOC-1 participate in a pathway-regulating synaptic function, we examined the role for NSF in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, we found that mutations in dysbindin precluded homeostatic synaptic plasticity elicited by acute blockage of postsynaptic receptors. This dysbindin mutant phenotype is fully rescued by presynaptic expression of either dysbindin or Drosophila NSF. However, neither reduction of NSF alone or in combination with dysbindin haploinsufficiency impaired homeostatic synaptic plasticity. Our results demonstrate that dysbindin/BLOC-1 expression defects result in altered cellular content of proteins of the vesicle fusion apparatus and therefore influence synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Ann. Hum. Genet. 2016 Jan 80: 38-49 |
| PMID | 26474449 |
| Title | Practical Experience of the Application of a Weighted Burden Test to Whole Exome Sequence Data for Obesity and Schizophrenia. |
| Abstract | For biological and statistical reasons it makes sense to combine information from variants at the level of the gene. One may wish to give more weight to variants which are rare and those that are more likely to affect function. A combined weighting scheme, implemented in the SCOREASSOC program, was applied to whole exome sequence data for 1392 subjects with schizophrenia and 982 with obesity from the UK10K project. Results conformed fairly well with null hypothesis expectations and no individual gene was strongly implicated. However, a number of the higher ranked genes appear plausible candidates as being involved in one or other phenotype and may warrant further investigation. These include MC4R, NLGN2, CRP, DONSON, GTF3A, IL36B, ADCYAP1R1, ARSA, DLG1, SIK2, SLAIN1, UBE2Q2, ZNF507, CRHR1, MUSK, NSF, SNORD115, GDF3 and HIBADH. Some individual variants in these genes have different frequencies between cohorts and could be genotyped in additional subjects. For other genes, there is a general excess of variants at many different sites so attempts at replication would be more difficult. Overall, the weighted burden test provides a convenient method for using sequence data to highlight genes of interest. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | J Neural Transm (Vienna) 2016 Feb -1: -1 |
| PMID | 26856328 |
| Title | SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond. |
| Abstract | Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 23 | Front Psychol 2016 -1 7: 707 |
| PMID | 27242619 |
| Title | A Two-Factor Model Better Explains Heterogeneity in Negative Symptoms: Evidence from the Positive and Negative Syndrome Scale. |
| Abstract | Acknowledging separable factors underlying negative symptoms may lead to better understanding and treatment of negative symptoms in individuals with schizophrenia. The current study aimed to test whether the negative symptoms factor (NSF) of the Positive and Negative Syndrome Scale (PANSS) would be better represented by expressive and experiential deficit factors, rather than by a single factor model, using confirmatory factor analysis (CFA). Two hundred and twenty individuals with schizophrenia spectrum disorders completed the PANSS; subsamples additionally completed the Brief Negative Symptom Scale (BNSS) and the Motivation and Pleasure Scale-Self-Report (MAP-SR). CFA results indicated that the two-factor model fit the data better than the one-factor model; however, latent variables were closely correlated. The two-factor model's fit was significantly improved by accounting for correlated residuals between N2 (emotional withdrawal) and N6 (lack of spontaneity and flow of conversation), and between N4 (passive social withdrawal) and G16 (active social avoidance), possibly reflecting common method variance. The two NSF factors exhibited differential patterns of correlation with subdomains of the BNSS and MAP-SR. These results suggest that the PANSS NSF would be better represented by a two-factor model than by a single-factor one, and support the two-factor model's adequate criterion-related validity. Common method variance among several items may be a potential source of measurement error under a two-factor model of the PANSS NSF. |
| SCZ Keywords | schizophrenia, schizophrenic |