Role of Synaptotagmins in Synaptic Plasticity in the Hippocampus

突触结合蛋白在海马突触可塑性中的作用

• 批准号: 8647667
• 负责人: Di Wu
• 金额: $ 5.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647667
• 关键词: AMPA Receptors; Acute; Address; Affect; Binding; Binding Sites; Brain; Calcium; Calcium Binding; Calcium-Binding Proteins; Carrying Capacities; Cell membrane; Cells; Communication; Complex; DNA; Dependovirus; Disadvantaged; Disease; Electrophysiology (science); Event; Excitatory Synapse; Exocytosis; Goals; Health; Hippocampus (Brain); Injection of therapeutic agent; Lead; Learning; Lentivirus; Link; Long-Term Potentiation; Maintenance; Mediating; Membrane; Membrane Fusion; Membrane Protein Traffic; Memory; Mental Depression; Mental disorders; Modeling; Molecular; Mutate; N-Methyl-D-Aspartate Receptors; Neurologic; Neurons; Post-Traumatic Stress Disorders; Postsynaptic Membrane; Presynaptic Terminals; Process; Property; Proteins; Pyramidal Cells; Receptor Activation; Research; Resistance; Role; SNAP receptor; Schizophrenia; Series; Slice; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Techniques; Testing; Vertebral column; Viral; base; cofactor; experience; gain of function; hippocampal pyramidal neuron; in vivo; insight; knock-down; lentiviral-mediated; mutant; neurotransmitter release; novel; postsynaptic; presynaptic; prevent; protein complex; public health relevance; research study; response; sensor; small hairpin RNA; synaptic function; synaptotagmin; trafficking; transmission process

DESCRIPTION (provided by applicant): Learning and memory requires use-dependent changes in synaptic function and transmission, a process known as synaptic plasticity. Many mental disorders such as schizophrenia, depression, and post-traumatic stress disorder may be linked to abnormalities in synaptic plasticity. One leading model of synaptic plasticity is long-term potentiation (LTP), which proposes that NMDA receptor activation enhances AMPA receptor mediated transmission to increase the strength of excitatory synapses. Despite decades of research, many aspects of the molecular mechanism underlying LTP remain unclear. The proposed study will test the hypothesis that calcium binding proteins known as synaptotagmins regulate the trafficking of AMPA receptors to the postsynaptic membrane. Presynaptic synaptotagmins are known to bind calcium and trigger neurotransmitter release. This study will use in vivo viral-mediated knockdown and replacement of synaptotagmins in CA1 pyramidal cells of the hippocampus. Electrophysiological recordings will be performed in acute hippocampal slices to determine the effect of these manipulations on LTP and basal transmission. Overall, these experiments will elucidate mechanisms of postsynaptic membrane trafficking and how they are involved in synaptic plasticity. Understanding these mechanisms may one day lead to new treatments for a variety of psychiatric disorders.

描述（由申请人提供）：学习和记忆需要突触功能和传递的使用依赖性变化，这一过程称为突触可塑性。许多精神疾病，如精神分裂症，抑郁症和创伤后应激障碍可能与突触可塑性异常有关。突触可塑性的一个主要模型是长时程增强（LTP），其提出NMDA受体激活增强AMPA受体介导的传递以增加兴奋性突触的强度。尽管经过几十年的研究，LTP的分子机制的许多方面仍然不清楚。这项拟议中的研究将检验一种假设，即钙结合蛋白（称为突触结合蛋白）调节AMPA受体向突触后膜的转运。已知突触前突触结合蛋白结合钙并触发神经递质释放。本研究将使用体内病毒介导的敲低和替换海马CA1锥体细胞中的突触结合蛋白。将在急性海马切片中进行电生理记录，以确定这些操作对LTP和基础传输的影响。总之，这些实验将阐明突触后膜运输的机制，以及它们如何参与突触可塑性。了解这些机制可能有一天会导致各种精神疾病的新疗法。