title: Rapid direct excitation and long-lasting enhancement of NMDA response by group I metabotropic glutamate receptor activation of hypothalamic melanin-concentrating hormone neurons.
abstract: The effect of group I metabotropic glutamate receptor (mGluR1 and mGluR5) activation on identified melanin-concentrating hormone (MCH) neurons was studied using patch-clamp recording in hypothalamic slices from green fluorescent protein-expressing transgenic mice. S-3,5-dihydroxyphenylglycine (DHPG), a selective group I mGluR agonist, depolarized MCH cells and increased spike frequency. The mGluR-mediated depolarization was not blocked with tetrodotoxin but was significantly reduced by replacement of extracellular Na+ with Tris, by Ni2+ or the Na+/Ca2+ exchanger blocker KB-R7943, or with BAPTA in the pipette, consistent with a mechanism based on activation of the Na+/Ca2+ exchanger. DHPG also decreased potassium currents. DHPG-induced depolarization was reduced by either mGluR1 or mGluR5 antagonists, suggesting involvement of both receptor subtypes. DHPG-induced depolarization desensitized; blockade of mGluR1 prevented the desensitization. Group I mGluR activation enhanced NMDA-evoked currents; this enhancement was remarkably long lasting and could be blocked by protein kinase A or C blockers. DHPG potentiated electrically evoked NMDA receptor-mediated postsynaptic currents, and mGluR5 antagonists blocked this action. Group I mGluRs increased spontaneous EPSCs in MCH neurons, possibly by stimulation of nearby mGluR-expressing hypocretin neurons. We found no tonic activation of mGluRs. However, electrical stimulation produced a slow inward current, which could be blocked by group I mGluR antagonists, suggesting high, but not low, levels of synaptically released glutamate activated mGluRs. Together, group I mGluRs increase MCH neuron activity by multiple presynaptic and postsynaptic mechanisms, suggesting mGluRs may therefore play a role in hypothalamic signaling relating to MCH neuron modulation of food intake and energy metabolism.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Anthony N
authors.initials: AN
authors.lastname: van den Pol
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D007028:Hypothalamic Hormones / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D008543:Melanins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010907:Pituitary Hormones / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D016202:N-Methylaspartate; C019463:melanin-concentrating hormone