Coupled LTP-dependent trafficking of synaptic SK channels and NMDARs

突触 SK 通道和 NMDAR 的耦合 LTP 依赖性运输

• 批准号: 8289226
• 负责人: JOHN P ADELMAN
• 金额: $ 31万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289226
• 关键词: 14-3-3 Proteins; Affect; Antibodies; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Brain; Brain Diseases; C-terminal; Calcium-Activated Potassium Channel; Cell model; Cells; Chemicals; Chemosensitization; Chinese Hamster Ovary Cell; Cognition Disorders; Cognitive; Coupled; Cyclic AMP-Dependent Protein Kinases; DNA Sequence Rearrangement; Dendritic Spines; Electrophysiology (science); Endocytosis; Endosomes; Epitopes; Excitatory Postsynaptic Potentials; Family; Hippocampus (Brain); Hour; Immunoelectron Microscopy; In Vitro; Intervention; Knockout Mice; Learning; Light; Link; Long-Term Potentiation; Measures; Membrane Potentials; Memory; Modeling; Molecular; N-Methylaspartate; Neurons; Pathway interactions; Peptides; Phosphorylation; Point Mutation; Preparation; Process; Proteins; Recovery; Relative (related person); Research; Scaffolding Protein; Serine; Slice; Synapses; Synaptic plasticity; Testing; Time; Vertebral column; Vesicle; Western Blotting; Whole-Cell Recordings; Work; base; clinical application; density; design; hippocampal pyramidal neuron; in vivo; innovation; memory encoding; mutant; neurotransmission; novel; overexpression; postsynaptic; reconstitution; research study; response; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Synaptic Ca2+-activated K+ channels, SK2 channels, influence neurotransmission, synaptic plasticity, and learning and memory. Blocking SK channel activity facilitates synaptic plasticity and learning and memory while overexpressing SK2 or pharmacologically increasing SK channel activity impairs these processes. We discovered the molecular and cellular mechanisms that are likely responsible for the effects of SK2 channels on synaptic plasticity, the leading model for cellular changes underlying learning and memory. We showed that the activity of SK2 channels in the dendritic spines of hippocampal CA1 pyramidal neurons is coupled to NMDAR activity. Synaptically evoked Ca2+ entry into spines activates synaptic SK2 channels that repolarize the spine membrane potential, thereby favoring Mg2+ re-block of NMDARs, and thus limiting Ca2+ influx through NMDARs that is crucial to the induction of synaptic plasticity. In addition we showed that plasticity-dependent trafficking of SK2 channels itself contributes to the expression of NMDAR-dependent long-term potentiation. New results suggest that SK2 channel trafficking is linked to NMDAR trafficking that is orchestrated and coordinated by a novel family of synaptic scaffolding proteins to affect synaptic dynamics. We will use an integrated repertoire of electrophysiology in fresh brain slice preparations and recordings from transfected cells, biochemical pull-down assays and reconstitutions experiments, and innovative immuno-electron microscopy to examine the molecular and cellular mechanisms that engender the orchestrated trafficking of SK2 channels and NMDARs. The results have profound implications for novel interventional strategies to treat a wide range of cognitive disorders. PUBLIC HEALTH RELEVANCE: Long-term synaptic plasticity is widely thought to be the cellular substrate for learning and memory. The proposed research will illuminate novel pathways and molecules employed by neurons in the brain to orchestrate cellular rearrangements that engender synaptic plasticity. Therefore, this work will reveal potential therapeutic targets for a wide range of cognitive and other brain disorders.

描述（由申请人提供）：突触 Ca2+ 激活的 K+ 通道、SK2 通道影响神经传递、突触可塑性以及学习和记忆。阻断 SK 通道活性有利于突触可塑性以及学习和记忆，而过度表达 SK2 或通过药理学增加 SK 通道活性会损害这些过程。我们发现了可能导致 SK2 通道对突触可塑性影响的分子和细胞机制，突触可塑性是学习和记忆基础细胞变化的主要模型。我们发现海马 CA1 锥体神经元树突棘中 SK2 通道的活性与 NMDAR 活性耦合。突触诱发的 Ca2+ 进入棘激活突触 SK2 通道，使棘膜电位重新极化，从而有利于 Mg2+ 重新阻断 NMDAR，从而限制 Ca2+ 通过 NMDAR 流入，这对于诱导突触可塑性至关重要。此外，我们还发现 SK2 通道的可塑性依赖性运输本身有助于 NMDAR 依赖性长时程增强的表达。新的结果表明，SK2 通道运输与 NMDAR 运输有关，NMDAR 运输由新型突触支架蛋白家族精心策划和协调，以影响突触动力学。我们将在新鲜脑切片制备和转染细胞记录、生化下拉分析和重构实验以及创新的免疫电子显微镜中使用电生理学的综合手段来检查引起 SK2 通道和NMDAR。这些结果对于治疗各种认知障碍的新型介入策略具有深远的影响。 公共健康相关性：长期突触可塑性被广泛认为是学习和记忆的细胞基础。拟议的研究将阐明大脑中神经元用来协调细胞重排从而产生突触可塑性的新途径和分子。因此，这项工作将揭示广泛的认知和其他脑部疾病的潜在治疗靶点。