Biphasic Somatic A-Type K⁺ Channel Downregulation Mediates Intrinsic Plasticity in Hippocampal CA1 Pyramidal Neurons

Since its original description, the induction of synaptic long-term potentiation (LTP) has been known to be accompanied by a lasting increase in the intrinsic excitability (intrinsic plasticity) of hippocampal neurons. Recent evidence shows that dendritic excitability can be enhanced by an activity-dependent decrease in the activity of A-type K+ channels. In the present manuscript, we examined the role of A-type K+ channels in regulating intrinsic excitability of CA1 pyramidal neurons of the hippocampus after synapse-specific LTP induction. In electrophysiological recordings we found that LTP induced a potentiation of excitability which was accompanied by a two-phased change in A-type K+ channel activity recorded in nucleated patches from organotypic slices of rat hippocampus. Induction of LTP resulted in an immediate but short lasting hyperpolarization of the voltage-dependence of steady-state A-type K+ channel inactivation along with a progressive, long-lasting decrease in peak A-current density. Blocking clathrin-mediated endocytosis prevented the A-current decrease and most measures of intrinsic plasticity. These results suggest that two temporally distinct but overlapping mechanisms of A-channel downregulation together contribute to the plasticity of intrinsic excitability. Finally we show that intrinsic plasticity resulted in a global enhancement of EPSP-spike coupling.自其首次被报道以来，突触长时程增强（synaptic long-term potentiation, LTP）的诱导过程已被证实会伴随海马神经元内在兴奋性的持久升高，该过程又被称为内在可塑性（intrinsic plasticity）。最新研究证据表明，树突兴奋性可通过活动依赖性的A型钾离子通道（A-type K+ channels）活性降低得以增强。本研究中，我们针对突触特异性LTP诱导后，A型钾离子通道在调控海马CA1锥体神经元内在兴奋性中的作用展开了探究。在电生理记录实验中，我们发现LTP诱导会引发兴奋性增强，同时在大鼠海马器官型脑片的带核膜片标本中记录到的A型钾离子通道活性呈现出双时相变化：LTP诱导后，稳态A型钾离子通道失活的电压依赖性会出现即刻但仅短暂持续的超极化偏移，与此同时峰值A电流密度则会出现渐进性的持久降低。阻断网格蛋白介导的内吞作用（clathrin-mediated endocytosis）可阻止A电流的降低以及绝大多数内在可塑性相关指标的变化。上述结果提示，两种时序上相互独立但机制存在重叠的A型钾离子通道下调途径，共同介导了内在兴奋性的可塑性调控。最后我们证实，内在可塑性会导致兴奋性突触后电位-锋电位耦合（EPSP-spike coupling）的全局性增强。