DOWN-REGULATION OF MGLUR5 BY ANTISENSE DEOXYNUCLEOTIDES ALTERS PHARMACOLOGICAL RESPONSES TO APPLICATIONS OF ACPD IN THE RAT HIPPOCAMPUS

Metabotropic glutamate receptors are thought to be important regulator s of synaptic transmission and plasticity in the hippocampus. The meta botropic glutamate receptor subtype mGluR5 is expressed in hippocampal pyramidal neurons but its function remains unknown due to the lack of selective pharmacological blockers. We inhibited the synthesis of mGl uR5 with antisense oligonucleotides injected into the hippocampus in v ivo. The functional effects of altered mGluR5 expression were measured electrophysiologically in the CA1 region of the hippocampus during ap plications of the metabotropic agonist 1S,3R-ACPD (50 mu M) to hippoca mpal slices from injected animals. The results show a concomitant redu ction of the mGluR5 receptor protein and physiological effects in the hippocampus. The major effect found in the antisense-treated animals w as the lack of an excitatory action normally produced by 1S,3R-ACPD. A nother effect attributed to metabotropic glutamate receptors, depressi on of synaptic transmission, had a more rapid onset, but unchanged mag nitude, while long-term potentiation remained unchanged. The specifici ty and effectiveness of the antisense treatment were confirmed using m ismatched oligonucleotides and immunoblotting. We conclude that the me tabotropic glutamate receptor subtype mGluR5 plays a major role in the regulation of cell. excitability in the hippocampus without directly affecting synaptic transmission or long-term potentiation. Moreover, i n vivo applications of antisense deoxynucleotides are a useful approac h in studies of neurotransmitter receptor subtypes. (C) 1997 Academic Press.