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.
Major depressive disorder is one of the most common mental disorders with a prevalence of nearly 20%. Epilepsy is the third most common neurological disorder and shows a strong comorbidity with mood disorders. This project will explore common neurobiological mechanisms in animal models for depression and epilepsy by focusing on an ion channel (the h channel) that has been associated with both diseases.
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