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，SK2通道，影响神经传递，突触可塑性和学习记忆。阻断SK通道活性有助于突触可塑性和学习记忆，而过度表达SK2或通过药物增加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中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+进入脊柱激活突触SK2通道，使脊柱膜电位重新极化，从而有利于Mg2+重新阻断NMDARs，从而限制Ca2+通过NMDARs的内流，这对诱导突触可塑性至关重要。此外，我们发现SK2通道的可塑性依赖性运输本身有助于nmdar依赖性长期增强的表达。新的研究结果表明，SK2通道运输与NMDAR运输有关，NMDAR运输是由一个新的突触支架蛋白家族精心策划和协调的，以影响突触动力学。我们将在新鲜脑切片制备和转染细胞的记录中使用综合电生理学，生化下拉试验和重构实验，以及创新的免疫电子显微镜来检查产生SK2通道和NMDARs的精心运输的分子和细胞机制。这一结果对治疗多种认知障碍的新型干预策略具有深远的意义。

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.