| 1 | Behav Brain Funct 2005 Aug 1: 15 |
|---|---|
| PMID | 16131404 |
| Title | Association study of polymorphisms in synaptic vesicle-associated genes, SYN2 and CPLX2, with schizophrenia. |
| Abstract | The occurrence of aberrant functional connectivity in the neuronal circuit is one of the integrative theories of the etiology of schizophrenia. Previous studies have reported that the protein and mRNA levels of the synapsin 2 (SYN2) and complexin 2 (CPLX2) genes were decreased in patients with schizophrenia. Synapsin 2 and complexin 2 are involved in synaptogenesis and the modulation of neurotransmitter release. This report presents a study of the association of polymorphisms of SYN2 and CPLX2 with schizophrenia in the Korean population. Six single nucleotide polymorphisms (SNPs) and one 5-bp insertion/deletion in SYN2 and five SNPs in CPLX2 were genotyped in 154 Korean patients with schizophrenia and 133 control patients using direct sequencing or restriction fragment length polymorphism analysis. An intermarker linkage disequilibrium map was constructed for each gene. Although there was no significant difference in the genotypic distributions and allelic frequencies of either SYN2 or CPLX2 polymorphisms between the schizophrenia and control groups, the two-way haplotype analyses revealed significant associations with the disease (P < 0.05 after Bonferroni correction). The three-way haplotype analyses also revealed a significant association of SYN2 with schizophrenia (P < 0.001 after Bonferroni correction). These results suggest that both SYN2 and CPLX2 may confer susceptibility to schizophrenia in the Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr. Res. 2006 Feb 82: 185-9 |
| PMID | 16442780 |
| Title | No association of complexin1 and complexin2 genes with schizophrenia in a Japanese population. |
| Abstract | Several investigations suggest that complexin may be a schizophrenia-susceptibility factor. We conducted a genetic association analysis between complexin genes (CPLX1 and CPLX2) and schizophrenia in Japanese patients (377 cases and 341 controls). Ten and eleven haplotype-tagging (ht)SNPs in CPLX1 and CPLX2, respectively, were selected. Only one htSNP (rs930047 in CPLX2) in allele-wise analysis showed significance, and even this disappeared with an increased sample size (563 cases and 519 controls: P = .757). Haplotype-wise analysis showed a weak association with a combination of htSNPs in CPLX2 (P = .0424), but this may be a result of type I error due to multiple testing. Our results suggest that complexin genes do not play a major role in schizophrenia in Japanese patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Arch. Gen. Psychiatry 2010 Sep 67: 879-88 |
| PMID | 20819981 |
| Title | Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. |
| Abstract | schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected] Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in CPLX2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Arch. Gen. Psychiatry 2010 Sep 67: 879-88 |
| PMID | 20819981 |
| Title | Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. |
| Abstract | schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected] Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in CPLX2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Genes Brain Behav. 2010 Aug 9: 592-602 |
| PMID | 20412316 |
| Title | Complexin2 null mutation requires a 'second hit' for induction of phenotypic changes relevant to schizophrenia. |
| Abstract | schizophrenia is a devastating disease that affects approximately 1% of the population across cultures. Its neurobiological underpinnings are still unknown. Accordingly, animal models of schizophrenia often lack construct validity. As concordance rate in monozygotic twins amounts to only 50%, environmental risk factors (e.g. neurotrauma, drug abuse, psychotrauma) likely act as necessary 'second hit' to trigger/drive the disease process in a genetically predisposed individual. Valid animal models would have to consider this genetic-environmental interaction. Based on this concept, we designed an experimental approach for modeling a schizophrenia-like phenotype in mice. As dysfunction in synaptic transmission plays a key role in schizophrenia, and complexin2 (CPLX2) gene expression is reduced in hippocampus of schizophrenic patients, we developed a mouse model with CPLX2 null mutation as genetic risk factor and a mild parietal neurotrauma, applied during puberty, as environmental 'second hit'. Several months after lesion, CPLX2 null mutants showed reduced pre-pulse inhibition, deficit of spatial learning and loss of inhibition after MK-801 challenge. These abnormalities were largely absent in lesioned wild-type mice and non-lesioned CPLX2 null mutants. Forced alternation in T-maze, object recognition, social interaction and elevated plus maze tests were unaltered in all groups. The previously reported mild motor phenotype of CPLX2 null mutants was accentuated upon lesion. MRI volumetrical analysis showed a decrease of hippocampal volume exclusively in lesioned CPLX2 null mutants. These findings provide suggestive evidence for the 'second hit' hypothesis of schizophrenia and may offer new tools for the development of advanced treatment strategies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Genes Brain Behav. 2010 Aug 9: 592-602 |
| PMID | 20412316 |
| Title | Complexin2 null mutation requires a 'second hit' for induction of phenotypic changes relevant to schizophrenia. |
| Abstract | schizophrenia is a devastating disease that affects approximately 1% of the population across cultures. Its neurobiological underpinnings are still unknown. Accordingly, animal models of schizophrenia often lack construct validity. As concordance rate in monozygotic twins amounts to only 50%, environmental risk factors (e.g. neurotrauma, drug abuse, psychotrauma) likely act as necessary 'second hit' to trigger/drive the disease process in a genetically predisposed individual. Valid animal models would have to consider this genetic-environmental interaction. Based on this concept, we designed an experimental approach for modeling a schizophrenia-like phenotype in mice. As dysfunction in synaptic transmission plays a key role in schizophrenia, and complexin2 (CPLX2) gene expression is reduced in hippocampus of schizophrenic patients, we developed a mouse model with CPLX2 null mutation as genetic risk factor and a mild parietal neurotrauma, applied during puberty, as environmental 'second hit'. Several months after lesion, CPLX2 null mutants showed reduced pre-pulse inhibition, deficit of spatial learning and loss of inhibition after MK-801 challenge. These abnormalities were largely absent in lesioned wild-type mice and non-lesioned CPLX2 null mutants. Forced alternation in T-maze, object recognition, social interaction and elevated plus maze tests were unaltered in all groups. The previously reported mild motor phenotype of CPLX2 null mutants was accentuated upon lesion. MRI volumetrical analysis showed a decrease of hippocampal volume exclusively in lesioned CPLX2 null mutants. These findings provide suggestive evidence for the 'second hit' hypothesis of schizophrenia and may offer new tools for the development of advanced treatment strategies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Int. J. Dev. Neurosci. 2011 May 29: 225-36 |
| PMID | 20888897 |
| Title | Molecular evidence that cortical synaptic growth predominates during the first decade of life in humans. |
| Abstract | Theories concerning the pathology of human neurodevelopmental disorders that emerge in adolescence, such as schizophrenia, often hypothesize that there may be a failure of normal cortical synaptic loss or pruning. However, direct evidence that synaptic regression is a major developmental event in the adolescent human cortex is limited. Furthermore, developmental work in rodents suggested that synaptic regression in adolescence is not a major feature of cortical development. Thus, we set out to determine when and to what extent molecular markers of synaptic terminals [synaptophysin (SYP), SNAP-25, syntaxin1A (STX1A), and vesicle-associated membrane protein 1 (VAMP1)] are reduced during postnatal human life spanning from 1 month to 45 years (n = 69) using several different quantitative methods, microarray, qPCR and immunoblotting. We found little evidence for a consistent decrease in synaptic-related molecular markers at any time point, but instead found clear patterns of gradual increases in expression of some presynaptic markers with postnatal age (including SNAP-25, VAMP1 and complexin 1 (CPLX1) mRNAs and 6/6 presynaptic proteins evaluated). A measure of synaptic plasticity [growth-associated protein of 43 kDa (GAP-43)] was elevated in neonates, and continued robust expression throughout life. Since CPLX1 protein is enriched in inhibitory terminals we also tested if the protein product of complexin 2 (CPLX2), which is enriched in excitatory neurons, is more specifically reduced in development. In contrast to CPLX1, which showed a steady increase in both mRNA and protein levels during postnatal development (both r > 0.58, p < 0.001), CPLX2 mRNA decreased from infants to toddlers (r = -0.56, p < 0.001), while CPLX2 protein showed a steady increase until young adulthood (r = 0.55, p < 0.001). Furthermore, we found that indices of the dendrites [microtubule associated protein 2 (MAP2)] and spines (spinophilin and postsynaptic density protein of 95 kDa (PSD95)] showed some evidence of reduction over time at the mRNA level but the opposite pattern, of a developmental increase, was found for PSD95 and spinophilin protein levels. Taken together, the postnatal changes in molecular components of synapses supports the notion that growth and strengthening of synaptic elements is a major developmental event occurring in the frontal cortex throughout childhood and that maintenance of steady state levels of synapse-associated molecules may predominate during human adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Eur Arch Psychiatry Clin Neurosci 2012 Apr 262: 199-205 |
| PMID | 22120873 |
| Title | Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. |
| Abstract | The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Recent Adv DNA Gene Seq 2014 -1 8: 30-4 |
| PMID | 25564026 |
| Title | Risk and protective effects of the complexin-2 gene and gene-environment interactions in schizophrenia. |
| Abstract | schizophrenia (SCZ) is a multifactorial chronic and disabling mental disease. The specific genetic variants contributing to disease complex phenotype are largely unknown. Growing amount of evidence suggested that aberrant synaptic connectivity contributes to SCZ pathogenesis. From this point of view, complexin-2, a presynaptic regulatory protein, represents here a special interest, since it has been recently shown that genetic variants of the CPLX2 gene may affect current cognitive performance in patients with SCZ. A specific objective of this study was to evaluate if tagging single nucleotide polymorphisms (rs3892909, rs1366116) of gene encoding complexin-2 protein (CPLX2) linked to SCZ and to examine their relationships with complexin-2 blood levels. DNA samples of 260 patients with SCZ and 260 sex- and age-matched healthy controls were genotyped for the selected polymorphisms by application of polymerase chain reaction with sequence-specific primers, and concentration of complexin-2 in the blood plasma was determined using the enzymelinked immunosorbent assay. All study subjects were unrelated Armenians. According to the obtained results, in the patients group both the frequency distribution and carriage rate of the CPLX2 rs1366116*T minor allele were higher than in controls. On the contrary, the frequency distribution and carriage rate of the CPLX2 rs3892909*T minor allele in control group were higher than in patients. This data suggested that the presence of the CPLX2 rs1366116*T allele increases susceptibility to SCZ, whereas the rs3892909*T allele of the CPLX2 decreases the risk of SCZ. Furthermore, we found that CPLX2 rs1366116*T heterozygosity is associated with earlier disease onset. No difference between complexin-2 plasma levels in patients and controls and no significant interaction between complexin-2 plasma levels and CPLX2 genotypes in both groups were observed. In summary, we concluded that the CPLX2 rs1366116*T variant represents a risk factor of SCZ, and that, at the same time, the CPLX2 rs3892909*T variant is protective against SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Eur Arch Psychiatry Clin Neurosci 2015 Mar 265: 137-45 |
| PMID | 25297695 |
| Title | Complexin2 modulates working memory-related neural activity in patients with schizophrenia. |
| Abstract | The specific contribution of risk or candidate gene variants to the complex phenotype of schizophrenia is largely unknown. Studying the effects of such variants on brain function can provide insight into disease-associated mechanisms on a neural systems level. Previous studies found common variants in the complexin2 (CPLX2) gene to be highly associated with cognitive dysfunction in schizophrenia patients. Similarly, cognitive functioning was found to be impaired in CPLX2 gene-deficient mice if they were subjected to maternal deprivation or mild brain trauma during puberty. Here, we aimed to study seven common CPLX2 single-nucleotide polymorphisms (SNPs) and their neurogenetic risk mechanisms by investigating their relationship to a schizophrenia-related functional neuroimaging intermediate phenotype. We examined functional MRI and genotype data collected from 104 patients with DSM-IV-diagnosed schizophrenia and 122 healthy controls who participated in the Mind Clinical Imaging Consortium study of schizophrenia. Seven SNPs distributed over the whole CPLX2 gene were tested for association with working memory-elicited neural activity in a frontoparietal neural network. Three CPLX2 SNPs were significantly associated with increased neural activity in the dorsolateral prefrontal cortex and intraparietal sulcus in the schizophrenia sample, but showed no association in healthy controls. Since increased working memory-related neural activity in individuals with or at risk for schizophrenia has been interpreted as 'neural inefficiency,' these findings suggest that certain variants of CPLX2 may contribute to impaired brain function in schizophrenia, possibly combined with other deleterious genetic variants, adverse environmental events, or developmental insults. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Biol. Psychiatry 2015 Sep 78: 361-73 |
| PMID | 25662103 |
| Title | Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia. |
| Abstract | Synaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15 schizophrenia cases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE). In the first cohort, syntaxin, Munc18-1, and Cplx1, but not VAMP, CPLX2, or synaptotagmin, were twofold enriched in SNAP25 immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from cohort 1 (OFC: +45%; anterior cingulate cortex: +44%) and cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (-37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%) and downregulated 550-kDa Cplx1-containing oligomers (-24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables. The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |