Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia

精神分裂症树突棘可塑性异常的分子机制

基本信息

批准号：
8608434
负责人：
Peter Penzes
金额：
$ 65.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-20 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608434
关键词：
Accounting Adolescent Affect Amino Acids Autistic Disorder Biological Models Brain Brain imaging Cell model Cell physiology Cerebral cortex Code Cognition Cognitive Cognitive deficits Confocal Microscopy Data Dendritic Spines Disease Electroporation Excitatory Synapse Exons Genes Glutamate Receptor Glutamates Heritability Human Genetics Image Individual Knowledge Measures Mediating Modeling Molecular Morphology Mus Mutation NRG1 gene Neurobiology Neurons Pathogenesis Pathway interactions Patients Phenotype Proteins Reporting Research Schizophrenia Siblings Structure Susceptibility Gene Synapses Synaptic Transmission Testing Therapeutic Intervention Thick Validation Variant Vertebral column base density frontal lobe gray matter human subject in utero insight mouse model multidisciplinary novel peer protein function rare variant therapeutic target translational approach two-photon

项目摘要

DESCRIPTION (provided by applicant): Multiple lines of evidence support a key role for abnormal synaptic connectivity in schizophrenia, but the molecular mechanisms underlying its pathogenesis are not known. Understanding these mechanisms may allow us to identify new targets for therapeutic intervention, especially early in the course of illness. The application wil focus on dendritic spines as cellular substrates of brain connectivity, because the majority of excitatory synapses are located on spines, and reduced spine density has been extensively documented in schizophrenia. Mounting evidence indicating that known schizophrenia susceptibility genes regulate spines and that regulators of spine plasticity are implicated in schizophrenia, strongly support the model that perturbations in the molecular network underlying spine plasticity are critically involved in the pathogenesis of schizophrenia. However, the mechanisms through which genetic alterations in this network underlie specific neurobiological phenotypes related to schizophrenia are not known. Recent data indicates that rare variants (including amino acid mutations) cumulatively account for a significant fraction of the "missing heritability" in schizophrenia, and cluster in gene networks that control synapses. Because a large fraction of such mutations are estimated to impair protein function, many are expected to cause brain circuit alterations. Thus, we propose that by identifying, testing for association, and characterizing rare variants enriched in schizophrenia, we will provide critical new insights into disease pathogenesis, because such mutations provide detailed knowledge about the affected molecular and cellular functions. Based on our preliminary data, we hypothesize that rare coding variants in genes that control dendritic spine plasticity, cumulativel enriched in subjects with schizophrenia, disrupt cortical connectivity and impact neuromorphological and cognitive measures in carriers. Using a multidisciplinary translational approach that combines human genetics, molecular and electrophysiological studies in cellular models, functional validation in mice, and cognitive assessment and structural brain imaging in patients, we will pursue these specific aims: 1) To assess the cellular impact of mutations in spine plasticity genes identified in schizophrenia subjects. 2) To determine the impact of mutations in spine plasticity genes on glutamatergic synaptic transmission. 3) To determine the impact of mutations in spine plasticity genes on cortical ultrastructure and functional connectivit in mice. 4) To assess the relationships between mutations in spine plasticity genes and phenotypic measures in patients.

描述（由申请人提供）：多种证据支持异常突触连接在精神分裂症中的关键作用，但其发病机制背后的分子机制尚不清楚。了解这些机制可能使我们能够确定治疗干预的新目标，尤其是在病程早期。该申请将重点关注树突棘作为大脑连接的细胞基质，因为大多数兴奋性突触位于树突棘上，并且树突棘密度降低已在精神分裂症中得到广泛记录。越来越多的证据表明，已知的精神分裂症易感基因调节脊柱，并且脊柱可塑性的调节因子与精神分裂症有关，这有力地支持了这样的模型：脊柱可塑性分子网络的扰动与精神分裂症的发病机制密切相关。然而，该网络中的遗传改变构成与精神分裂症相关的特定神经生物学表型的机制尚不清楚。最近的数据表明，罕见变异（包括氨基酸突变）累积起来占了精神分裂症“遗传性缺失”的很大一部分，并且聚集在控制突触的基因网络中。由于估计此类突变中的很大一部分会损害蛋白质功能，因此许多突变预计会导致脑回路改变。因此，我们建议通过鉴定、测试关联性和表征精神分裂症中富含的罕见变异，我们将为疾病发病机制提供重要的新见解，因为此类突变提供了有关受影响的分子和细胞功能的详细知识。根据我们的初步数据，我们假设控制树突棘可塑性的基因中的罕见编码变异在精神分裂症受试者中累积富集，破坏皮质连接并影响携带者的神经形态和认知测量。使用多学科转化方法，结合人类遗传学、细胞模型中的分子和电生理学研究、小鼠的功能验证以及患者的认知评估和结构脑成像，我们将追求以下具体目标：1）评估突变对细胞的影响在精神分裂症受试者中发现的脊柱可塑性基因。 2）确定脊柱可塑性基因突变对谷氨酸能突触传递的影响。 3) 确定脊柱可塑性基因突变对小鼠皮质超微结构和功能性连接的影响。 4) 评估脊柱可塑性基因突变与患者表型测量之间的关系。