| 1 | Hum. Mol. Genet. 2005 Aug 14: 2369-85 |
|---|---|
| PMID | 16000319 |
| 标题 | 复合素I敲除小鼠的深度共济失调遮盖了一个复杂的表型，其中包括探索性和习惯性缺陷。 |
| 抽象的 | 复合蛋白是突触前蛋白，它们结合了SNARE复合物，它们调节神经递质释放。许多研究报告了精神病中复合蛋白的变化（schizophreniaand depression) and neurodegenerative disorders (Huntington's disease, Wernicke's encephalopathy and Parkinson's disease). Here, we characterize the behavioural phenotype ofCPLX1knockout (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- / - 小鼠还显示其他行为缺陷，尤其是在复杂行为中。它们在修饰和饲养行为方面存在缺陷，并在几种不同的范式中显示出探索减少。它们还显示出反映情感反应性的任务缺陷。他们未能习惯于监禁，并在暴露于水时表现出“恐慌”的反应。在行为中看到的异常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关键字 | schizophrenia |
| 2 | 精神分裂。res。2006年2月82日：185-9 |
| PMID | 16442780 |
| 标题 | 在日本人群中，没有复杂素1和复合素2基因与精神分裂症的关联。 |
| 抽象的 | 几项调查表明，复杂蛋白可能是schizophrenia- 敏感性因子。我们在复合蛋白基因之间进行了遗传关联分析（CPLX1和CPLX2）和schizophrenia日本患者（377例病例和341例对照）。十个和11个单倍型标签（HT）SNPCPLX1分别选择了CPLX2。等位基因分析中只有一个HTSNP（CPLX2中的RS930047）显示出显着性，甚至随着样本量的增加而消失了（563例和519个对照：P = .757）。单倍型的分析表明，与CPLX2中HTSNP的组合的结合较弱（P = .0424），但这可能是由于多次测试而导致的I型误差的结果。我们的结果表明，复杂蛋白基因在schizophrenia在日本患者中。 |
| SCZ关键字 | schizophrenia |
| 3 | Neurobiol. Dis. 2007 Mar 25: 483-95 |
| PMID | 17188502 |
| 标题 | Early motor development is abnormal in complexin 1 knockout mice. |
| 抽象的 | 复合蛋白I的表达在许多神经系统疾病中失调schizophreniaand depression. Adult complexin 1 knockout (CPLX1(-/-)) mice are severely ataxic and show deficits in exploration and emotional reactivity. Here, we evaluated early behavioural development ofCPLX1（-/-） 老鼠。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 developschizophreniain 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 andschizophrenia。 |
| SCZ关键字 | schizophrenia |
| 4 | Hum. Mol. Genet. 2007 Oct 16: 2288-305 |
| PMID | 17652102 |
| 标题 | Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal. |
| 抽象的 | Complexins are presynaptic proteins that modulate neurotransmitter release. Abnormal expression of complexin 1 (CPLX1）在几种神经退行性和精神疾病中可以看出，其中令人不安的社会行为很普遍。其中包括帕金森氏病，阿尔茨海默氏病，schizophrenia, major depressive illness and bipolar disorder. We wondered whether changes inCPLX1expression contribute to the psychiatric components of the diseases in whichCPLX1特异表达。研究这个问题,我们检查了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 juvenileCPLX1(-/-) mice to swim, they showed no evidence of cognitive impairment in the two-choice swim tank. In contrast, although olfactory discrimination inCPLX1（ - / - ）小鼠正常，CPLX1（ - / - ）小鼠在食品偏好任务的社会传播中失败了，这是另一种认知范式。这是由于社会互动异常而不是认知障碍，焦虑或新恐惧症。当我们直接测试社会行为时CPLX1（ - / - ）小鼠未能表现出对社会新颖性的偏爱。此外，在一个居民范式中，男性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（ - / - ）小鼠在社会行为方面有明显的缺陷。因此，大脑中复合蛋白1水平的异常可能导致该蛋白失调的人类疾病的心理社会方面。 |
| SCZ关键字 | schizophrenia |
| 5 | int。J. Dev。Neurosci。2011年5月29日：225-36 |
| PMID | 20888897 |
| 标题 | 分子证据表明，皮质突触生长在人类生命的头十年中占主导地位。 |
| 抽象的 | 关于在青春期出现的人类神经发育障碍的病理学的理论，例如schizophrenia，通常假设可能会导致正常皮质突触损失或修剪失败。但是，直接证据表明突触回归是青春期人皮层中的主要发育事件是有限的。此外，啮齿动物的发育工作表明，青春期突触回归不是皮质发育的主要特征。因此，我们着手确定突触末端的分子标记[突触蛋白（SYP），SNAP-25，Snap-25，Syntaxin1a（STX1A）和囊泡相关的膜蛋白1（VAMP1）]的分子标记。从1个月到45年（n = 69）使用几种不同的定量方法，即微阵列，QPCR和免疫印迹。我们几乎没有发现在任何时间点突触相关的分子标记均保持一致的证据，而是发现某些具有产后年龄的突触前标记的表达逐渐增加的明显模式（包括SNAP-25，VAMP1和COMPCERTIN 1）（CPLX1）评估的mRNA和6/6突触前蛋白）。新生儿的突触可塑性[43 kDa（GAP-43）的生长相关蛋白（GAP-43）]的量度升高，并在整个生命中持续稳健地表达。自从CPLX1protein 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 toCPLX1, 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关键字 | schizophrenia |
| 6 | Eur Arch Psychiatry Clin Neurosci 2012年4月262日：199-205 |
| PMID | 22120873 |
| 标题 | Case-control association study for 10 genes in patients with schizophrenia: influence of 5HTR1A variation rs10042486 on schizophrenia and response to antipsychotics. |
| 抽象的 | 这项研究的目的是研究10个基因中的一组单核苷酸多态性（SNP）之间的可能关联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关键字 | schizophrenia |
| 7 | J. Neurosci. 2014 Oct 34: 14375-87 |
| PMID | 25339750 |
| 标题 | PGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. |
| 抽象的 | Accumulating 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)、结构(神经丝重链(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关键字 | schizophrenia |
| 8 | Nat. Neurosci. 2015 Jul 18: 1008-16 |
| PMID | 26005852 |
| 标题 | 精神分裂症风险基因产物miR-137改变了突触前可塑性。 |
| 抽象的 | Noncoding variants in the human MIR137 gene locus increaseschizophrenia具有全基因组意义的风险。但是，这些风险等位基因的功能后果尚不清楚。在这里，我们检查了携带的人类神经元，这些神经元具有MIR137中与疾病相关的四个单核苷酸多态性的次要等位基因。我们观察到与主要等位基因携带细胞相比，miR137水平升高。MicroRNA-137功能的获益导致突触前靶基因复合素-1的下调（CPLX1），NSF和Synaptotagmin-1（SYT1），导致囊泡释放受损。在体内，miR-137功能的增益导致突触囊泡分布的变化，苔藓纤维长期增强的诱导受损以及海马依赖性学习和记忆的缺陷。通过隔离内源性miR-137，我们能够改善突触表型。此外，恢复SYT1表达的恢复部分恢复了突触可塑性，表明SYT1作为miR-137靶标的重要性。我们的数据提供了有关miR-137失调可能损害海马中突触可塑性的机制的新见解。 |
| SCZ关键字 | schizophrenia |
| 9 | Schizophr Bull 2015 Dec -1: -1 |
| PMID | 26683626 |
| 标题 | 皮质PGC-1？ - 依赖性转录本在验尸组织中降低了精神分裂症患者的死后组织。 |
| 抽象的 | 转录共激活因子过氧化物组增殖物激活受体 - 伽马共激活剂1-α（PGC-1？）与多种神经系统和精神疾病有关schizophrenia，但是它参与这些疾病的病理生理学尚不清楚。在小鼠中进行的实验揭示了一组发育调节的皮质PGC-1？依赖性转录本参与钙缓冲（Parvalbumin，PV），同步神经递质释放（Synaptotototagmin 2，Syt2; Complexin 1，Complexin 1，sytt2; Complexin 1，Syttaptagin;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 andschizophrenia患者并发现PGC-1？依赖性转录本没有变化，而PGC-1？而控制受试者具有高PGC-1？表达表现出很高的PV和NEFH表达，schizophreniasubjects with high PGC-1? expression did not, suggesting dissociation between PGC-1? expression and these targets inschizophrenia。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 inschizophrenia，及其转录水平预测了PGC-1？依赖性目标schizophrenia。有趣的是，PGC-1之间的正相关关系？和PV，SYT2或CPLX1expression was lost inschizophreniapatients with low NRF-1 expression, suggesting that NRF-1 is a critical predictor of these genes in disease. These data suggest thatschizophrenia涉及PGC-1的中断？和/或NRF-1相关的转录程序，以及增强PGC-1活性的方法？或转录调节剂（如NRF-1）应考虑恢复正常基因程序并改善皮质功能的目标。 |
| SCZ关键字 | schizophrenia |
| 10 | 生物。精神病学2015年9月78日：361-73 |
| PMID | 25662103 |
| 标题 | 在精神分裂症中，在眶额和前扣带回皮质中增加了SNARE蛋白 - 蛋白质相互作用。 |
| 抽象的 | 突触功能障碍schizophrenia可能与可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白（Syntaxin，Syntaxin，突触体相关蛋白25 [SNAP25]，囊泡相关膜相关膜蛋白[VAMP]）形成分子复合神经脱落的神经脱落蛋白质的异常表达或功能。这种异常对有效的弹力异构体形成的影响知之甚少。我们调查了推定的圈套功能障碍，以及圈套绑定伙伴Munc18-1，Complexins（CPLX）1/2和突触的可能作用schizophrenia。 Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15schizophreniacases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE). 在第一个队列中，语法素，munc18-1和CPLX1，但不是vamp，cplx2或Synaptotagmin，两倍富集于SNAP25免疫沉淀产品中schizophreniaOFC 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 inschizophrenia来自队列1的样品（OFC： +45％；前扣带回皮质： +44％）和队列2（OFC： +40％），OFC中的70 kDa snap25-vamp二聚体（-37％）。上调200千圈的圈套 -CPLX1（+65％）和下调550 kDaCPLX1-containing oligomers (-24%) inschizophrenia通过BN-PAGE确定OFC。这些发现未通过验尸间隔，抗精神病药物或其他潜在混淆变量来解释。 这些发现支持上调上调的圈套复合物形成的假设schizophreniaOFC, possibly favored by enhanced affinity for Munc18-1 and/orCPLX1。这些更改为schizophrenia。 |
| SCZ关键字 | schizophrenia |