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The Journal of Neuroscience, November 26, 2003, 23(34):10884-10891

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Cellular/Molecular
The Sleep-Modulating Peptide Cortistatin Augments the h-Current in Hippocampal Neurons

Paul Schweitzer, Samuel G. Madamba, and George R. Siggins

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Cortistatin (CST) is a sleep-modulating peptide found exclusively in the brain. Although CST is closely related to somatostatin (SST) and binds to SST receptors, CST has effects on sleep and neuronal activity in cortex and hippocampus that differ from SST. To uncover the cellular mechanisms affected by CST, we studied the electrophysiological postsynaptic effects of CST and assessed its interaction with SST on hippocampal CA1 pyramidal neurons. CST altered intrinsic membrane properties and occluded SST effects, indicating that both peptides similarly augment the sustained K⁺ M- and leak-currents (I_M and I_K(L)). In the presence of SST, however, CST elicited an additional inwardly rectifying component in the hyperpolarized range. This effect was unaffected by barium, used to block K⁺ currents, but was completely prevented by the selective h-current (I_h) blocker ZD7288. CST, but not SST, selectively increased I_h in a concentration-dependent manner by augmenting its maximum conductance. CST did not shift the I_h activation curve, and the peptide effect was unaffected by a membrane-permeable analog of cAMP. We conclude that CST and SST similarly increase K⁺ conductances in hippocampal neurons, most likely by activating SST receptors. However, CST additionally augments I_h, a voltage-dependent current that plays a key role in the modulation of synaptic integration and regulates oscillatory activity. Our results indicate that CST targets a specific conductance unaffected by SST to modulate cellular mechanisms implicated in sleep regulation.

Key words: somatostatin; M-current; potassium current; cation current; hippocampus; slice

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Received June 4, 2003; revised October 8, 2003; accepted October 9, 2003.

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