Modulation of Dendritic K+ Channels in Hippocampus

锥体神经元接受数以万计的兴奋性和抑制性突触输入到树突。树突动态地改变这些突触的强度，并协调它们，以一种尚未被很好理解的方式产生输出。在以前的工作中，我们发现在海马CA1区锥体神经元的树突中存在非常高密度的瞬时A型K+通道。这些通道阻止了动作电位在树突中的启动，限制了动作电位向树突的反向传播，并降低了兴奋性突触事件的幅度。因此，这些通道对这些神经元的整体兴奋性施加了强大的控制。 在前一个资助时期的研究中，我们发现这些通道的活性至少被两个重要的第二信使系统PKA和PKC所降低，并且这些通路作用于MAPK的上游。此外，我们有初步证据表明，CaMKII调节A通道的表达。在上一次资助期间的其他工作表明，A通道在突触可塑性的诱导和表达中都发挥了作用，这些通道的变化可能是癫痫过度兴奋的原因之一。这一更新应用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，并研究这些通道在长时程增强(LTP)过程中可能发生变化的机制。我们还将探索在颞叶癫痫急性模型中树突状A-通道和H-通道的变化。这个 具体目的是：1)检验小斜树突内A型K+通道受特定神经递质和第二信使系统调节的假说；2)检验LTP过程中树突状细胞兴奋性局部改变是由于A通道下调的假说；3)检验A通道的树突分布受CaMKII调控的假说；4)检验癫痫发生部分是由于电压门控的树突通道改变所致的假说。 拟议的实验将利用大鼠和小鼠的海马片、树突状膜片钳 录音和荧光成像。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本信息。

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, A-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 downregulation 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 epileptogenesisis 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.