Coupled LTP-dependent trafficking of synaptic SK channels and NMDARs

描述(申请人提供)：突触钙激活的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通道的活动有助于突触的可塑性和学习记忆，而SK2的过度表达或药物增加的SK通道活性则损害这些过程。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，在海马CA1区锥体神经元树突棘中SK2通道的活动与NMDAR的活动是耦合的。突触诱发的钙离子进入脊髓激活突触SK2通道，使脊膜电位重新极化，从而有利于NMDARs的镁离子再阻断，从而限制钙离子通过NMDARs的内流，这对突触可塑性的诱导至关重要。此外，我们还表明，依赖可塑性的SK2通道的运输本身有助于NMDAR依赖的长时程增强的表达。新的结果表明，SK2通道的运输与NMDAR的运输有关，NMDAR的运输是由一个新的突触支架蛋白家族协调和协调的，以影响突触动力学。我们将使用新鲜脑片制备和转基因细胞的记录、生化下拉分析和重组实验以及创新的免疫电子显微镜来研究产生SK2通道和NMDAR协调运输的分子和细胞机制。这一结果对治疗广泛的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.