Mechanisms of Central Neuron Synaptogenesis

中枢神经元突触发生的机制

基本信息

批准号：
8389529
负责人：
ANN M CRAIG
金额：
$ 24.13万
依托单位：
UNIVERSITY OF BRITISH COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389529
关键词：
Alzheimer&apos s Disease Amyloid beta-Protein Precursor Animal Model Antibodies Autistic Disorder Axon Behavior Behavioral Behavioral Assay Binding Biochemical Biochemistry Biological Assay Brain Brain region COS Cells Cadherins Caenorhabditis elegans Calcium-Binding Domain Cell Fractionation Cell physiology Chemicals Cleaved cell Coculture Techniques Cognition Cognition Disorders Cognitive Collaborations Communication Complementary DNA Complex Confocal Microscopy Data Defect Development Disease Electron Microscopy Electrophysiology (science)Epilepsy Epitopes Family Family Study Future Gene Family Genes Glutamates Goals Grant Health Hippocampus (Brain)Homologous Gene Hour Human Individual Injury Integral Membrane Protein Knock-out Knockout Mice Lead Learning Length Link Lower Organism Mental Retardation Mental disorders Modeling Molecular Molecular Genetics Morphology Mus Mutation Natural regeneration Neurodegenerative Disorders Neurons Neurotransmitters Parkinson Disease Pattern Peptide Hydrolases Pharmaceutical Preparations Physiological Physiology Process Property Protease Inhibitor Proteins Proteolysis Recruitment Activity Regulation Reporting Research Role Schizophrenia Series Signal Transduction Site Stroke Structure Surface Susceptibility Gene Synapses Synaptic Transmission Synaptic plasticity Tertiary Protein Structure Variant Western Blotting autism spectrum disorder base brain cell brain morphology classical conditioning cognitive function design extracellular fluorescence imaging gamma-Aminobutyric Acid gene function improved in vivo injured memory process memory recall morris water maze nervous system disorder novel object recognition overexpression postsynaptic presynaptic protein function repaired research study synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Brain development requires orchestrated formation of connections between nerve cells. These synaptic connections are the main units of communication in the brain, where chemical neurotransmitter signaling occurs. This proposal is on synaptic organizing proteins, genes that function as master regulators of synaptic development. Such proteins alone can trigger formation of nerve cell connections. In preliminary studies, from an unbiased screen we identified a new protein that triggers development of presynaptic connections in contacting nerve cell processes. It is one of a family of 3 highly related proteins. The proposed experiments will assess the ability of these 3 synaptic organizing proteins to drive formation of nerve cell connections of different neurotransmitter types, and will identify protein domains responsible. These novel synaptic organizing proteins can be cleared by extracellular proteolysis. Preliminary data suggests that cleavage abolishes synaptic organizing activity; thus we will study how cleavage is regulated. Finally, a major aim is to use a combination of mouse molecular genetics, fluorescence imaging, biochemistry, electrophysiology, and behavioral assays to determine the importance of these genes in brain development and synaptic function. This combined in vivo approach will allow an understanding of how these genes contribute to brain wiring, synaptic composition, structure, and function, and how changes in specific synapses result in behavioral changes. Such approaches often result in useful models for psychiatric disorders. The central hypothesis is that these genes are crucial for organizing synaptic development, for recruiting molecular components essential for proper synaptic structure and function in brain circuits important for cognition. Variation in one of these genes is linked to word recall ability, and lower organisms lacking the single homologous gene are deficient in learning. Furthermore, variants in the major synaptic organizing gene families studied to date, neuroligins and neurexins, predispose to autism spectrum disorders, schizophrenia, and mental retardation. Thus, in studying these synaptic organizing genes, we hope to increase our understanding of the molecular basis for cognitive disorders and to help design rational drug treatments. As triggers for building synaptic connections, these genes may also have implications for a number of neurological disorders from epilepsy and stroke to Alzheimer's and Parkinson's diseases. It may be possible to harness the ability of these genes to trigger formation of nerve cell connections to repair and regenerate the lost and injured connections in these debilitating disorders.

描述（由申请人提供）：大脑发育需要神经细胞之间精心形成的连接。这些突触连接是大脑中发生化学神经递质信号传导的主要通讯单位。该提案涉及突触组织蛋白，即作为突触发育主要调节因子的基因。这些蛋白质本身就可以触发神经细胞连接的形成。在初步研究中，我们通过公正的筛选发现了一种新的蛋白质，它可以触发接触神经细胞过程中突触前连接的发展。它是 3 个高度相关的蛋白质家族之一。拟议的实验将评估这 3 种突触组织蛋白驱动不同神经递质类型的神经细胞连接形成的能力，并将识别负责的蛋白域。这些新型突触组织蛋白可以通过细胞外蛋白水解作用来清除。初步数据表明，分裂消除了突触组织活动；因此我们将研究裂解是如何调控的。最后，一个主要目标是结合小鼠分子遗传学、荧光成像、生物化学、电生理学和行为测定来确定这些基因在大脑发育和突触功能中的重要性。这种组合的体内方法将有助于了解这些基因如何影响大脑接线、突触组成、结构和功能，以及特定突触的变化如何导致行为变化。这些方法通常会产生有用的精神疾病模型。核心假设是，这些基因对于组织突触发育、招募对认知很重要的大脑回路中正确的突触结构和功能至关重要的分子成分至关重要。这些基因之一的变异与单词记忆能力有关，缺乏单一同源基因的低等生物体在学习方面存在缺陷。此外，迄今为止研究的主要突触组织基因家族神经连接蛋白和神经毒素的变异，容易导致自闭症谱系障碍、精神分裂症和精神发育迟滞。因此，通过研究这些突触组织基因，我们希望增进对认知障碍分子基础的理解，并帮助设计合理的药物治疗。作为建立突触连接的触发因素，这些基因也可能对许多神经系统疾病（从癫痫和中风到阿尔茨海默病和帕金森病）产生影响。或许可以利用这些基因触发神经细胞连接形成的能力，以修复和再生这些使人衰弱的疾病中丢失和受损的连接。