Coupled LTP-dependent trafficking of synaptic SK channels and NMDARs

描述（由申请人提供）：突触Ca2+激活的K+通道，SK 2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和学习记忆，而过度表达SK 2或过度增加SK通道活性则会损害这些过程。我们发现了可能负责SK2通道对突触可塑性影响的分子和细胞机制，这是学习和记忆细胞变化的主要模型。我们发现，海马CA1区锥体神经元树突棘中的SK 2通道的活性与NMDAR活性相耦合。突触诱发的Ca 2+进入棘激活突触SK 2通道，其恢复棘膜电位，从而有利于Mg 2+重新阻断NMDAR，并因此限制Ca 2+通过NMDAR的内流，这对诱导突触可塑性至关重要。此外，我们发现SK2通道本身的可塑性依赖性运输有助于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运输由一个新的突触支架蛋白家族协调和协调，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中使用电生理学的综合剧目，生化下拉测定和重组实验，以及创新的免疫电子显微镜检查产生SK2通道和NMDAR的协调贩运的分子和细胞机制。这些结果对治疗各种认知障碍的新型干预策略具有深远的意义。 公共卫生相关性：长期突触可塑性被广泛认为是学习和记忆的细胞基质。这项拟议中的研究将阐明大脑中神经元所采用的新途径和分子，以协调产生突触可塑性的细胞重排。因此，这项工作将揭示广泛的认知和其他大脑疾病的潜在治疗靶点。

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.