Metabotropic glutamate receptors modulate the NMDA- and AMPA-induced gene expression in neocortical interneurons.
Group I metabotropic glutamate receptors (mGluRIs) can be colocalized with ionotropic glutamate receptors in postsynaptic membranes. We have investigated whether mGluRIs alter the gene transcription induced by N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptors in rat neocortical gamma-aminobutyric acid (GABA) interneurons. In cultures of dissociated interneurons, the mGluRI antagonists LY367385 and MPEP reduced the increase in phosphorylation of the transcription factor CREB induced by NMDA as well as the expression of the proenkephalin (PEnk) gene. In contrast, they enhanced the AMPA-induced CREB phosphorylation and PEnk gene expression. Stimulation of the mGluRIs was due to network activity that caused the release of endogenous glutamate and could be blocked by tetrodotoxin. In organotypic cultures of neocortex, endogenous glutamate enhanced the PEnk gene expression by acting on NMDA and AMPA receptors. These effects were modulated via mGluRIs. In patch-clamp experiments and in biochemical studies on receptor density, stimulation of mGluRIs acutely affected NMDA receptor currents but had no long-term effect on NMDA receptor density at the cell surface. In contrast, stimulation of mGluRIs decreased the density of AMPA receptors located at the cell surface. Our results suggest that mGluRIs regulate the glutamate-induced gene expression in neocortical interneurons in a physiologically relevant manner.
Lindemeyer
Kerstin
K
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert Ludwigs University, Freiburg, Germany.
Leemhuis
Jost
J
Löffler
Steffen
S
Grass
Nina
N
Nörenberg
Wolfgang
W
Meyer
Dieter K
DK
D000818:Animals; D001710:Biotin; D015152:Blotting, Northern; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004594:Electrophysiology; D004745:Enkephalins / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology*; D019579:Neocortex / Q000166:cytology / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
D017362:Cyclic AMP Response Element-Binding Protein; D004745:Enkephalins; D018690:Excitatory Amino Acid Agonists; D011498:Protein Precursors; D012333:RNA, Messenger; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C029992:proenkephalin; D016202:N-Methylaspartate; D001710:Biotin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid