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The Journal of Neuroscience, October 24, 2007, 27(43):11560-11572; doi:10.1523/JNEUROSCI.2147-07.2007

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Behavioral/Systems/Cognitive
Rapid Direct Excitation and Long-Lasting Enhancement of NMDA Response by Group I Metabotropic Glutamate Receptor Activation of Hypothalamic Melanin-Concentrating Hormone Neurons

Hao Huang and Anthony N. van den Pol

Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: Anthony.vandenpol{at}yale.edu

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.

Key words: metabotropic glutamate receptor; melanin concentrating hormone; NMDA; food intake; hypothalamus; mice

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Received May 9, 2007; revised July 26, 2007; accepted Aug. 23, 2007.

Correspondence should be addressed to Anthony N. van den Pol, Department of Neurosurgery, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06520. Email: Anthony.vandenpol{at}yale.edu

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