Modulation of CA1 Neuronal Excitability by SK Channels.

描述（由申请人提供）：神经元兴奋性需要突触后电位的总和，以达到动作电位爆发传播的阈值。在海马CA1区锥体神经元中，小电导Ca~（2+）激活的K~+（SK）通道被认为是后超极化（AHP）的两个Ca~（2+）依赖性成分的基础。这些SK通道可被突触激活，提示它们可能参与兴奋性突触后电位（EPSP）的形成。通过调节EPSP的幅度和持续时间，SK通道活动可以确定突触后CA1神经元是否达到动作电位传播的阈值。通过调节动作电位爆发模式和EPSP，这些通道可能有助于CA1神经元在生理学中最基本的作用：学习和记忆的整合。与该提议一致的是观察到体内SK通道的药理学调节刺激小鼠的海马依赖性学习。三个不同的SK通道亚基，SK 1，SK 2和SK 3，已被克隆，并在CA 1神经元中表达。由于这些通道的潜在的神经生理学的重要性，本建议的总体目标是调查这些不同的SK通道亚基的AHP，尖峰频率适应，和CA1神经元的EPSP的生理贡献。为了测试，我将研究SK转基因小鼠，其中SK表达的调节急性和发育后的组织特异性的方式。

DESCRIPTION (provided by applicant): Neuronal excitability requires the summation of post-synaptic potentials to attain threshold for the propagation of a burst of action potentials. In CA1 hippocampal pyramidal neurons, small conductance Ca2+-activated K+ (SK) channels are believed to underlie the two Ca2+-dependent components of the afterhyperpolarization (AHP). These SK channels can be activated synaptically suggesting that they may contribue to excitatory post-synaptic potentials (EPSPs). By modulating both the magnitude and duration of EPSPs, SK channel activity may determine whether a post-synaptic CA1 neuron reaches threshold for action potential propagation. By modulating action potential bursting patterns and EPSPs, these channels potentially contribute to the most fundamental role of CA1 neurons in physiology: the integration of learning and memory. Consistent with this proposal is the observation that pharmacological modulation of SK channels in vivo stimulates hippocampal-dependent learning in mice. Three distinct SK channel subunits, SK1, SK2 and SK3, have been cloned and all are expressed in CA1 neurons. Because of the potential neurophysiologcal importance of these channels, the overall aim of this proposal is to investigate the physiological contribution of these different SK channel subunits to the AHP, spike frequency adaptation, and EPSPs of CA1 neurons. To test, I will investigate SK transgenic mice in which SK expression is regulated acutely and post-developmentally in a tissue specific manner.