Dendritic K+ Channels in Hippocampal Pyramidal Neurons

锥体神经元接受数以万计的兴奋性和抑制性突触输入到它们的树突上。 树突动态地改变这些突触的强度，并协调它们以不太清楚的方式产生输出。在以前的工作中，我们发现有一个非常高密度的瞬时，IA型钾通道在海马CA 1区锥体神经元树突。这些通道阻止树突中的动作电位起始，限制动作电位向树突的反向传播，并降低兴奋性突触事件的振幅。因此，这些通道对这些神经元的整体兴奋性施加了强有力的控制。 在上一个资助期的研究中，我们发现这些通道的活性被至少两个突出的第二信使系统PKA和PKC降低，并且这些途径作用于MAPK的上游。此外，我们有初步的证据表明，CaMKII调节A通道的表达。 在先前的资助期间的额外工作表明，A通道在突触可塑性的诱导和表达中发挥作用，并且这些通道的变化可能是癫痫过度兴奋的基础。该更新申请的总体目标是继续探索神经递质和第二信使对天然A通道的调节，并研究长时程增强（LTP）过程中这些通道可能发生变化的机制。我们还将探讨颞叶癫痫急性模型中树突状A通道和H通道的变化。具体目标是：1）验证小斜树突中A型K+通道受特定神经递质和第二信使系统调节的假设; 2）验证小斜树突中A型K+通道的局部变化与第二信使系统的调节有关的假设。 LTP期间树突兴奋性是由于A-通道的下调; 3）测试A-通道的树突分布受CaMK II调节的假设;和4）测试癫痫发生部分是由于树突电压门控通道的变化的假设。 拟进行的实验将利用大鼠和小鼠海马脑片、树突状膜片钳 记录和荧光成像。这些实验的结果将为颞叶癫痫、阿尔茨海默病、精神分裂症和抑郁症的研究提供重要的基础信息。

Pyramidal neurons receive tens of thousands of excitatory and inhibitory synaptic inputs onto their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. In previous work we found that there is a very high density of transient, IA-type K+ channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent action potential initiation in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce the amplitudes of excitatory synaptic events. The channels thus exert a powerful control over the overall excitability of these neurons. In studies during the previous funding period, we found that the activity of these channels is decreased by at least two prominent 2nd messenger systems, PKA and PKC, and that these pathways act upstream of MAPK. Furthermore, we have preliminary evidence that CaMKII regulates the expression of A-channels. Additional work during the previous grant suggests that A-channels play a role in both the induction and expression of synaptic plasticity, and that changes in these channels may underlie aspects of the hyperexcitability of epilepsy. The overall objective of this renewal application is to continue to explore the regulation of native A-channels by neurotransmitters and 2nd messengers and to investigate the mechanisms for possible changes in these channels during long-term potentiation (LTP). We will also explore changes in dendritic A-channels and h-channels in an acute model for temporal lobe epilepsy. The specific aims are: 1) to test the hypothesis that A-type K+ channels in small oblique dendrites are modulated by specific neurotransmitters and 2nd messenger systems; 2) to test the hypothesis that local changes in dendritic excitability during LTP are due to down-regulation of A-channels; 3) to test the hypothesis that the dendritic distribution of A-channels is regulated by CaMKII; and 4) to test the hypothesis that epileptogenesis is due in part to changes in dendritic, voltage-gated channels. The proposed experiments will utilize rat and mouse hippocampal slices, dendritic patch-clamp recordings, and fluorescence imaging. The results of these experiments will provide basic information important for studies of temporal lobe epilepsy, Alzheimer's disease, schizophrenia, and depression.