Cellular Information Processing in the Hippocampus

描述(由申请人提供)：有令人信服的证据表明哺乳动物的海马体参与学习和记忆以及某些神经和精神障碍。我们的长期目标是了解单个锥体神经元如何整合来自数以万计冲击其树突的突触的输入，从而参与海马体的正常和异常功能。在以前的工作中，我们发现了许多电压门控离子通道(如Na+、Ca~(2+)和K~+)的树突状表达，并展示了这些通道如何调节突触整合和突触可塑性的诱导和表达。我们还发现，其中几个树突通道，包括h通道，经历了活性相关的可塑性，称为本征可塑性， 它调节神经元的兴奋性。在颞叶癫痫(TLE)的动物模型中，我们发现树突状K+和h通道显著减少，最近我们发现在大鼠背侧海马区h通道的HCN1亚单位被敲除后，可以产生抗抑郁和抗焦虑的行为。从临床文献来看，癫痫患者的抑郁和焦虑似乎有很强的共同发病率。然而，h通道丢失发生在TLE中，h通道被敲除会产生抗抑郁行为，这一发现似乎与临床文献相矛盾。我们的初步数据表明，这种明显的矛盾可能是由于在这些疾病模型中背侧和腹侧海马体的不同受累。在此，我们建议确定1)沿整个海马背腹轴的单个锥体神经元的电生理特性，2)h通道和内向整流性K+通道在这些区域是否有差异表达，以及3)在颞叶癫痫和抑郁的动物模型中，这些通道是否以区域特异性的方式改变。这些实验将利用大鼠的海马脑片、体细胞和树突膜片钳电生理学、免疫组织化学和Western blotting。

DESCRIPTION (provided by applicant): There is compelling evidence for the involvement of the mammalian hippocampus in learning and memory as well as certain neurological and psychiatric disorders. Our long-term objective is to understand how single pyramidal neurons integrate input from the tens of thousands of synapses impinging on their dendrites and thereby participate in normal and abnormal functioning of the hippocampus. In previous work we discovered the dendritic expression of a number of voltage-gated ion channels (e.g., Na+, Ca2+, and K+) and demonstrated how these channels regulate both synaptic integration and the induction and expression of synaptic plasticity. We also found that several of these dendritic channels, including h channels, undergo activity-dependent plasticity, called Intrinsic Plasticity, which regulates the excitability of neurons. In animal models for temporal lobe epilepsy (TLE), we found a significant reduction in dendritic K+ and h channels, and recently we showed that a knockdown of the HCN1 subunit for h channels in dorsal hippocampus produces anti-depression and anti-anxiety like behaviors in rats. From the clinical literature there appears to be a strong co-morbidity for depression and anxiety in epilepsy. The findings that a loss of h channels occurs in TLE and a knockdown of h channels produces anti-depressive behaviors, however, appear to be contradictory with this clinical literature. Our preliminary data suggest that this apparent contradiction may be due to a different involvement of the dorsal and ventral hippocampus in these disease models. We propose here to determine 1) the electrophysiological properties of single pyramidal neurons along the entire dorsal-ventral axis of the hippocampus, 2) whether h channels and inward rectifier K+ channels are differentially expressed in these regions, and 3) whether these channels are altered in a region-specific manner in animal models for temporal lobe epilepsy and depression. The experiments will utilize hippocampal brain slices from rats, somatic and dendritic patch-clamp electrophysiology, and immunohistochemistry and western blotting.