Activity Dependent Modulation of SK2 Channels

描述（由申请人提供）：Schaffer侧支突触处突触强度的长时程增强（LTP）主要归因于α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体（AMPAR）的数量和生物物理性质的变化。小电导Ca ~（2+）激活的K ~+通道（SK ~ 2通道）在功能上与CA_1棘上的N-甲基-D-天冬氨酸受体（NMDAr）偶联，使其活性调节兴奋性突触后电位（EPSP）的形状并增加诱导LTP的阈值。阻断SK2通道可促进海马CA 1区神经元的可塑性， 海马依赖性学习任务的获得。此外，转基因小鼠CA 1神经元中过表达SK 2通道会损害突触可塑性和海马依赖性记忆编码的诱导。因此，SK2通道调节突触可塑性的诱导。我的初步数据显示，SK2通道也有助于LTP。在Schaffer侧支突触处诱导LTP消除了增强的突触中的SK 2通道活性。这种效应是由于SK2通道从突触后致密物（PSD）内化到脊柱中。阻断PKA或用代表含有三个已知PKA磷酸化位点的SK2的C末端结构域的肽透析的细胞阻断LTP诱导后SK2通道的内化。因此，AMPAR的增加和SK 2通道的减少结合联合收割机产生了LTP基础上的EPSP增加。SK 2通道可塑性对LTP的贡献约为14%。虽然这是一个显著的贡献，增加的AMPAR对EPSP的贡献占兴奋性增加的大部分。然而，SK2通道内吞作用在LTP诱导后的功能后果可能对随后的突触活动的影响更显着。CA 1神经元棘中的SK 2通道提供了一种负反馈，其通过NMDAr减弱Ca 2+内流。SK2通道介导的复极化效应的丧失将在随后的突触活动中显著增加通过NMDAr进入的Ca 2+的量（至少40%）。这将有效地促进塑性的诱导。因此，重要的是要确定SK2通道的命运，一旦他们从增强的棘和PKA信号机制参与。本研究旨在探讨突触可塑性和记忆形成的基本机制，为进一步认识突触可塑性和学习过程奠定基础。

DESCRIPTION (provided by applicant): Long term potentiation of synaptic strength (LTP) at Schaffer collateral synapses has largely been attributed to changes in the number and biophysical properties of a-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptors (AMPAr). Small conductance Ca2+ activated K+ channels (SK2 channels) are functionally coupled with N-methyl-D-aspartate receptors (NMDAr) in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials (EPSPs) and increases the threshold for induction of LTP. Blocking SK2 channels facilitates CA1 neuron plasticity in hippocampus and promotes animal acquisition of hippocampal dependent learning tasks. Moreover, overexpressing SK2 channels in CA1 neurons in transgenic mice impairs the induction of synaptic plasticity and hippocampal-dependent memory encoding. Therefore, SK2 channels modulate the induction of synaptic plasticity. My preliminary data show that SK2 channels additionally contribute to LTP. The induction of LTP at Schaffer collateral synapses abolishes SK2 channel activity in the potentiated synapses. This effect is due to SK2 channel intemalization from the postsynaptic density (PSD) into the spine. Blocking PKA or cell dialyzed with a peptide representing the C-terminal domain of SK2 that contains three known PKA phosphorylation sites blocks the intemalization of SK2 channels following LTP induction. Thus the increase in AMPAr and the decrease in SK2 channel combine to produce the increased EPSP underlying LTP. SK2 channel plasticity contributes ~14% to LTP. While this is a significant contribution, the increased AMPAr contribution to the EPSP accounts for the majority of the increased excitability. However, the functional consequence of SK2 channel endocytosis upon the induction of LTP may be more significant for the effect on subsequent synaptic activity. SK2 channels in the spines of CA1 neurons provide a negative feedback that attenuates the Ca2+ influx through NMDAr. The lost repolarizing effect mediated by the SK2 channels will profoundly increase the amount of Ca2+ entering through NMDAr (at least 40%) upon subsequent synaptic activity. This will effectively facilitate the induction of plasticity. Therefore, it is important to determine the fates of the SK2 channels once they are removed from potentiated spines and the PKA signaling mechanisms involved. This proposal is targeted to study the basic mechanisms of synaptic plasticity and memory formation, and will contribute to our fundamental knowledge in plasticity and learning process.