title: Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long-term depression in the nucleus accumbens via a CaMKII-dependent mechanism.
abstract: Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N-methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch-clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission. Blockade of NMDAR during but not after TS showed enhanced mGluR1/5-LTD induction, which is associated with its antagonism of TS-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation. The ability of NMDAR antagonists to promote mGluR1/5-LTD induction was mimicked by a selective CaMKII inhibitor KN-62. However, the induction of mGluR1/5-LTD by bath-applied agonist (S)-3,5-dihydrophenylglycine was not affected by NMDAR blockade. We also observed that NMDAR or CaMKII blockade during TS significantly blunted TS-induced increased serine/threonine phosphorylation of the scaffold protein Homer1b/c and resulted in an increased interaction of mGluR5 with the Homer1b/c. These results indicate that synaptically released glutamate during TS of excitatory afferents can activate both NMDAR and mGluR1/5 in NAc neurons concomitantly and that activation of NMDAR may stimulate CaMKII-mediated phosphorylation of Homer1b/c and impair the interaction between mGluR5 and Homer1b/c, thereby attenuating mGluR1/5-LTD induction. This study provides a novel molecular mechanism by which NMDAR could regulate mGluR5 function.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan 701, Taiwan. Chun19682003@yahoo.com.tw
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2