The relationship of cognitive performance to stress is described by an inverted U-shaped Yerkes-Dodson curve. This relationship is partially mediated by release of dopamine and/or norepinephrine, with downstream effects on cyclic AMP signaling through Gs protein coupled receptors. Cyclic AMP activates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which in turn have been shown to have a significant role in the development of stress-induced cognitive impairment. Drugs which inhibit one of the pathways activating HCN channels have been investigated for possible efficacy in improving attention and working memory. There is preliminary evidence to support a role of HCN in risk for depression, anxiety disorders and obsessive-compulsive disorder. However, the research literature is not consistent and a more recent report has not demonstrated a role for HCN channel genes in depression, neuroticism and cognitive function ( )

Kim and coworkers now report that knockdown of HCN1 channels in the dorsal hippocampal CA1 region of the brain leads to anxiolytic- and antidepressant-like behaviors in mouse models. Dorsal hippocampal CA1 activity was found to be enhanced as well as brain-derived neurotrophic factor (BDNF)-mTOR signaling after knockdown of the HCN1 channel.  Further work in human subjects is needed to assess the therapeutic potential of these effects for drugs targeting HCN channel pathways.

Kim CS, Chang PY, Johnston D: Enhancement of dorsal hippocampal activity by knockdown of HCN1 channels leads to anxiolytic- and antidepressant-like behaviors. Neuron 75(3): 503-516 (2012).

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