1Hum. Mol. Genet. 2005 Aug 14: 2369-85
TitleProfound ataxia in complexin I knockout mice masks a complex phenotype that includes exploratory and habituation deficits.
AbstractComplexins are presynaptic proteins that bind to the SNARE complex where they modulate neurotransmitter release. A number of studies report changes in complexins in psychiatric (schizophrenia and depression) and neurodegenerative disorders (Huntington's disease, Wernicke's encephalopathy and Parkinson's disease). Here, we characterize the behavioural phenotype of CPLX1 knockout (CPLX1-/-) mice. CPLX1-/- mice develop a strong ataxia in the absence of cerebellar degeneration. Although originally reported to die within 2-4 months after birth, when reared using an enhanced feeding regime, these mice survive normally (i.e. >2 years). CPLX1-/- mice show pronounced deficits in motor coordination and locomotion including abnormal gait, inability to run or swim, impaired rotarod performance, reduced neuromuscular strength, dystonia and resting tremor. Although the abnormal motor phenotype dominates their overt symptoms, CPLX1-/- mice also show other behavioural deficits, particularly in complex behaviours. They have deficits in grooming and rearing behaviour and show reduced exploration in several different paradigms. They also show deficits in tasks reflecting emotional reactivity. They fail to habituate to confinement and show a 'panic' response when exposed to water. The abnormalities seen in the behaviour of CPLX1-/- mice reflect those predicted from the distribution of complexin I in the brain. Our data show that complexin I is essential not only for normal motor function in mice, but also for normal performance of other complex behaviours. These results support the idea that altered expression of complexins in disease states may contribute to the symptomatology of disorders in which they are dysregulated.
SCZ Keywordsschizophrenia
2Schizophr. Res. 2006 Feb 82: 185-9
TitleNo association of complexin1 and complexin2 genes with schizophrenia in a Japanese population.
AbstractSeveral 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 Keywordsschizophrenia
3Neurobiol. Dis. 2007 Mar 25: 483-95
TitleEarly motor development is abnormal in complexin 1 knockout mice.
AbstractComplexin I expression is dysregulated in a number of neurological diseases including schizophrenia and depression. Adult complexin 1 knockout (CPLX1(-/-)) mice are severely ataxic and show deficits in exploration and emotional reactivity. Here, we evaluated early behavioural development of CPLX1(-/-) mice. CPLX1(-/-) mice showed marked abnormalities. They develop ataxia by post-natal day 7 (P7), and by P21 show marked deficits in tasks requiring postural skills and complex movement. These deficits are consistent with abnormalities in sensory and motor development found in infants that develop schizophrenia in later life. A role for complexin I depletion should be considered in diseases where deficits in early sensory and motor development exist, such as autism and schizophrenia.
SCZ Keywordsschizophrenia
4Hum. Mol. Genet. 2007 Oct 16: 2288-305
TitleComplexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal.
AbstractComplexins are presynaptic proteins that modulate neurotransmitter release. Abnormal expression of complexin 1 (CPLX1) is seen in several neurodegenerative and psychiatric disorders in which disturbed social behaviour is commonplace. These include Parkinsons's disease, Alzheimer's disease, schizophrenia, major depressive illness and bipolar disorder. We wondered whether changes in CPLX1 expression contribute to the psychiatric components of the diseases in which CPLX1 is dysregulated. To investigate this, we examined the cognitive and social behaviours of complexin 1 knockout mice (CPLX1(-/-)) mice. CPLX1(-/-) mice have a profound ataxia that limits their ability to perform co-ordinated motor tasks. Nevertheless, when we taught juvenile CPLX1(-/-) mice to swim, they showed no evidence of cognitive impairment in the two-choice swim tank. In contrast, although olfactory discrimination in CPLX1(-/-) mice was normal, CPLX1(-/-) mice failed in the social transmission of food preference task, another cognitive paradigm. This was due to abnormal social interactions rather than cognitive impairments, increased anxiety or neophobia. When we tested social behaviour directly, CPLX1(-/-) mice failed to demonstrate a preference for social novelty. Further, in a resident-intruder paradigm, male CPLX1(-/-) mice failed to show the aggressive behaviour that is typical of wild-type males towards an intruder mouse. Together our results show that in addition to the severe motor and exploratory deficits already described, CPLX1(-/-) mice have pronounced deficits in social behaviours. Abnormalities in complexin 1 levels in the brain may therefore contribute to the psycho-social aspects of human diseases in which this protein is dysregulated.
SCZ Keywordsschizophrenia
5Int. J. Dev. Neurosci. 2011 May 29: 225-36
TitleMolecular evidence that cortical synaptic growth predominates during the first decade of life in humans.
AbstractTheories 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 Keywordsschizophrenia
6Eur Arch Psychiatry Clin Neurosci 2012 Apr 262: 199-205
TitleCase-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics.
AbstractThe 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 Keywordsschizophrenia
7J. Neurosci. 2014 Oct 34: 14375-87
TitlePGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons.
AbstractAccumulating evidence strongly implicates the transcriptional coactivator peroxisome proliferator-activated receptor ? coactivator 1? (PGC-1?) in the pathophysiology of multiple neurological disorders, but the downstream gene targets of PGC-1? in the brain have remained enigmatic. Previous data demonstrate that PGC-1? is primarily concentrated in inhibitory neurons and that PGC-1? is required for the expression of the interneuron-specific Ca(2+)-binding protein parvalbumin (PV) throughout the cortex. To identify other possible transcriptional targets of PGC-1? in neural tissue, we conducted a microarray on neuroblastoma cells overexpressing PGC-1?, mined results for genes with physiological relevance to interneurons, and measured cortical gene and protein expression of these genes in mice with underexpression and overexpression of PGC-1?. We observed bidirectional regulation of novel PGC-1?-dependent transcripts spanning synaptic [synaptotagmin 2 (Syt2) and complexin 1 (CPLX1)], structural [neurofilament heavy chain (Nefh)], and metabolic [neutral cholesterol ester hydrolase 1 (Nceh1), adenylate kinase 1 (Ak1), inositol polyphosphate 5-phosphatase J (Inpp5j), ATP synthase mitochondrial F1 complex O subunit (Atp5o), phytanol-CoA-2hydroxylase (Phyh), and ATP synthase mitrochondrial F1 complex ? subunit 1 (Atp5a1)] functions. The neuron-specific genes Syt2, CPLX1, and Nefh were developmentally upregulated in an expression pattern consistent with that of PGC-1? and were expressed in cortical interneurons. Conditional deletion of PGC-1? in PV-positive neurons significantly decreased cortical transcript expression of these genes, promoted asynchronous GABA release, and impaired long-term memory. Collectively, these data demonstrate that PGC-1? is required for normal PV-positive interneuron function and that loss of PGC-1? in this interneuron subpopulation could contribute to cortical dysfunction in disease states.
SCZ Keywordsschizophrenia
8Nat. Neurosci. 2015 Jul 18: 1008-16
TitleThe schizophrenia risk gene product miR-137 alters presynaptic plasticity.
AbstractNoncoding 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 Keywordsschizophrenia
9Schizophr Bull 2015 Dec -1: -1
TitleCortical PGC-1?-Dependent Transcripts are Reduced in Postmortem Tissue From Patients With Schizophrenia.
AbstractThe transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1?) has been linked to multiple neurological and psychiatric disorders including schizophrenia, but its involvement in the pathophysiology of these disorders is unclear. Experiments in mice have revealed a set of developmentally-regulated cortical PGC-1?-dependent transcripts involved in calcium buffering (parvalbumin, PV), synchronous neurotransmitter release (synaptotagmin 2, Syt2; complexin 1, CPLX1) and axonal integrity (neurofilamaent heavy chain, Nefh). We measured the mRNA expression of PGC-1? and these transcripts in postmortem cortical tissue from control and schizophrenia patients and found a reduction in PGC-1?-dependent transcripts without a change in PGC-1?. While control subjects with high PGC-1? expression exhibited high PV and Nefh expression, schizophrenia subjects with high PGC-1? expression did not, suggesting dissociation between PGC-1? expression and these targets in schizophrenia. Unbiased analyses of the promoter regions for PGC-1?-dependent transcripts revealed enrichment of binding sites for the PGC-1?-interacting transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 mRNA expression was reduced in schizophrenia, and its transcript levels predicted that of PGC-1?-dependent targets in schizophrenia. Interestingly, the positive correlation between PGC-1? and PV, Syt2, or CPLX1 expression was lost in schizophrenia patients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease. These data suggest that schizophrenia involves a disruption in PGC-1? and/or NRF-1-associated transcriptional programs in the cortex and that approaches to enhance the activity of PGC-1? or transcriptional regulators like NRF-1 should be considered with the goal of restoring normal gene programs and improving cortical function.
SCZ Keywordsschizophrenia
10Biol. Psychiatry 2015 Sep 78: 361-73
TitleIncreased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia.
AbstractSynaptic 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 Keywordsschizophrenia