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The Journal of Neuroscience, June 15, 2003, 23(12):4951-4957
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Orexin Excites GABAergic Neurons of the Arcuate Nucleus by Activating the Sodium—Calcium Exchanger
Denis Burdakov, * Birgit Liss, * andFrances M. Ashcroft University Laboratory of Physiology, Oxford, OX1 3PT, United Kingdom
The neuropeptides orexins/hypocretins are essential for normal wakefulness and energy balance, and disruption of their function causes narcolepsy and obesity. Although much is known of the role of orexins in sleep/wake behavior, it remains unclear how they stimulate feeding and metabolism. One of the main targets of orexinergic neurons is the arcuate nucleus (ARC) of the hypothalamus, which plays a key role in feeding and energy homeostasis. By combining patch-clamp and RT-multiplex PCR analysis of individual neurons in mouse brain slices, we show that an electrophysiologically distinct subset of ARC neurons coexpress orexin receptors and glutamate decarboxylase-67 and are excited by orexin. Acting on postsynaptic orexin type 2 receptors, orexin activates a sodium—calcium exchange current, thereby depolarizing the cell and increasing its firing frequency. Because GABA is a potent stimulus for feeding, in both the ARC and its main projection site, these results suggest a mechanism for how orexin may control appetite.
Key words: orexin; hypocretin; arcuate nucleus; sleep; feeding; energy balance; neuropeptides; hypothalamus
Received Dec. 26, 2002; revised Mar. 4, 2003; accepted Mar. 9, 2003.
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