Knockdown of HCN1 channels in the dorsal hippocampal CA1 region

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Kim, Chung Sub

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The hippocampus is an integral brain region for affective disorders. HCN1 protein shows age-dependent increase in expression resulting in an increase in I[subscript h] in the dorsal hippocampal CA1 region. TRIP8b knockout mice lacking functional HCN channels as well as both HCN1 and HCN2 knockout mice have been shown to display antidepressant-like behaviors. The mechanisms or brain regions involved in these alterations in behavior, however, are not clear. We developed a lentiviral shRNA system to examine whether knockdown of HCN1 protein, and therefore h-channels, in the dorsal hippocampal CA1 region is sufficient to produce antidepressant-like effects. We found that silencing of HCN1 gene resulted in physiological changes consistent with a reduction of I[subscript h] and increased cellular excitability of CA1 pyramidal neurons. Rats infused with lentiviral-shRNA-HCN1 in the dorsal hippocampal CA1 region displayed antidepressant- and anxiolytic-like behaviors. Using voltage-sensitive dye imaging, we found that knockdown of HCN1 in the dorsal hippocampal CA1 region led to enhancement of hippocampal activity in large regions of the dorsal hippocampus. Our results demonstrate that changed hippocampal network activity by local manipulation of HCN1 channels in dorsal hippocampus led to anxiolytic- and antidepressant-like behaviors and suggest that HCN1 channels could be a potential target for treatment of anxiety and depression.




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