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 regulators of synaptic transmission and plasticity in the hippocampus. The metabotropic 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 mGluR5 with antisense oligonucleotides injected into the hippocampus in vivo. The functional effects of altered mGluR5 expression were measured electrophysiologically in the CA1 region of the hippocampus during applications of the metabotropic agonist 1S,3R-ACPD (50 microM) to hippocampal slices from injected animals. The results show a concomitant reduction of the mGluR5 receptor protein and physiological effects in the hippocampus. The major effect found in the antisensetreated animals was the lack of an excitatory action normally produced by 1S,3R-ACPD. Another effect attributed to metabotropic glutamate receptors, depression of synaptic transmission, had a more rapid onset, but unchanged magnitude, while long-term potentiation remained unchanged. The specificity and effectiveness of the antisense treatment were confirmed using mismatched oligonucleotides and immunoblotting. We conclude that the metabotropic 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, in vivo applications of antisense deoxynucleotides are a useful approach in studies of neurotransmitter receptor subtypes.