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The physiological activity of hypothalamic arcuate nucleus (ARC) neurons is critical for dynamic maintenance of body energy homeostasis, and its malfunction can result in common metabolic disorders, such as obesity. It is therefore of interest to determine which set of ion channels shapes electrical activity in the ARC. Whole-cell patch clamp of ARC neurons in mouse brain slices identified three electrophysiologically distinct types of neurons. These were distinguished by their rebound "signatures" after hyperpolarizing current injection in current clamp and by the presence of transient inward (Type-B neurons) or outward (Type-A and Type-C neurons) subthreshold voltage-gated currents in voltage-clamp recordings. In turn, the transient outward current (A-current) of Type-C neurons had a lower activation threshold and different time and voltage dependence of inactivation than that of Type-A neurons. The brain-gut peptide cholecystokinin (CCK) has long been recognized to control food intake, but how endogenous CCK modulates the activity of central appetite-regulating networks remains unresolved. Here, we show that low (picomolar) concentrations of CCK rapidly and reversibly slow the firing of ARC Type-C neurons. This effect is mediated by postsynaptic CCK-B receptors and is attributable to potentiation of the A-current. Our study thus identifies several fundamental biophysical mechanisms underlying the physiological activity of ARC neurons and suggests a novel mechanism by which endogenous CCK may control appetite.

Type

Journal article

Journal

J Neurosci

Publication Date

01/08/2002

Volume

22

Pages

6380 - 6387

Keywords

Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Calcium, Cholecystokinin, Dose-Response Relationship, Drug, Electric Stimulation, In Vitro Techniques, Membrane Potentials, Mice, Mice, Inbred C57BL, Neurons, Patch-Clamp Techniques, Phenotype, Potassium Channel Blockers, Potassium Channels, Reaction Time, Receptor, Cholecystokinin B, Receptors, Cholecystokinin, Tetrodotoxin