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海马体参与学习和记忆以及某些神经和精神疾病。我们的长期目标是了解单个锥体神经元如何整合来自撞击其树突的数万个突触的输入，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的树突状表达（例如，Na+，Ca2+和K+），并证明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，包括h通道在内的几种树突状通道经历了活性依赖性可塑性，称为内在可塑性， 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，在大鼠背海马中敲低h通道的HCN 1亚基可产生抗抑郁和抗焦虑样行为。从临床文献来看，癫痫患者的抑郁和焦虑似乎有很强的共病性。然而，在TLE中发生h通道的丢失和h通道的敲低产生抗抑郁行为的发现似乎与该临床文献相矛盾。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的背侧和腹侧海马体的不同参与。我们在这里提出，以确定1）单个锥体神经元的电生理特性沿着整个背腹轴的海马，2）是否h通道和内向整流K+通道在这些地区的差异表达，和3）是否这些通道改变在一个区域的特定方式在颞叶癫痫和抑郁症的动物模型。实验将利用大鼠海马脑切片、体细胞和树突膜片钳电生理学、免疫组织化学和蛋白质印迹。

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.