title: Orexin peptides enhance median preoptic nucleus neuronal excitability via postsynaptic membrane depolarization and enhancement of glutamatergic afferents.
abstract: Subpopulations of neurons in the median preoptic nucleus (MnPO) located within the lamina terminalis contribute to thermoregulatory, cardiovascular and hydromineral homeostasis, and sleep-promotion. MnPO is innervated by lateral hypothalamic neurons that synthesize and secrete the arousal-promoting and excitatory orexin (hypocretin) neuropeptides. To evaluate the hypothesis that orexins modulate the excitability of MnPO neurons, we used patch-clamp recording techniques applied in rat brain slice preparations to assess the effects of exogenously applied orexin A and orexin B peptides on their intrinsic and synaptic properties. Whole cell recordings under current-clamp mode revealed that 11/15 tested MnPO neurons responded similarly to either orexin A or B (500-1000 nM) with a slowly rising, prolonged (10-15 min) and reversible membrane depolarization. Under voltage-clamp mode, orexin applications induced a tetrodotoxin-resistant inward current of -7.2+/-1.6 pA, indicating a direct (postsynaptic) activation, with a time course similar to the observed membrane depolarization. The orexin-induced responses in 4/7 neurons were associated with a significant decrease in membrane conductance and the net orexin-induced current that reversed at -99+/-5 mV, suggesting closure of potassium channels. Orexins did not attenuate the properties of excitatory (n=4) or inhibitory (n=7) postsynaptic currents evoked by subfornical organ stimulation. By contrast, orexins applications induce a significant increase in both frequency and amplitude of spontaneous glutamatergic postsynaptic currents (5/7 cells) but had no influence on spontaneous GABAergic currents (6/6 cells). Thus, in addition to a direct postsynaptic receptor-mediated excitation, orexins can also increase the excitability of MnPO neurons via increasing their excitatory inputs, presumably through an orexin receptor-mediated excitation of local glutamatergic neurons whose axons project to MnPO neurons.
authors.affiliation: Neuroscience Program, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9. mkolaj@ohri.ca
authors.forename: M
authors.initials: M
authors.lastname: Kolaj
authors.forename: E
authors.initials: E
authors.lastname: Coderre
authors.forename: L P
authors.initials: LP
authors.lastname: Renaud
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D000068797:Orexins; D018408:Patch-Clamp Techniques / Q000379:methods; D011301:Preoptic Area / Q000166:cytology*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D018698:Glutamic Acid