MODIFICATION OF NMDA RECEPTOR CHANNELS AND SYNAPTIC TRANSMISSION BY TARGETED DISRUPTION OF THE NR2C GENE

A novel strain of mutant mouse has been generated with a deletion of t he gene encoding the NR2C subunit of the NMDA receptor, which is prima rily expressed in cerebellar granule cells. Patch-clamp recordings fro m granule cells in thin cerebellar slices were used to assess the cons equences of the gene deletion. In granule cells of wild-type animals, a wide range of single-channel conductances were observed (19-60 pS). The disruption of the NR2C gene results in the disappearance of low-co nductance NMDA receptor channels (<37 pS) normally expressed in granul e cells during developmental maturation. The NMDA receptor-mediated sy naptic current is markedlypotentiated in amplitude, but abbreviated in duration (with no net difference in total charge), acid the non-NMDA component of the synaptic current was reduced. We conclude that the NR 2C subunit contributes to functional heteromeric NMDA receptor-subunit assemblies at the messy fiber synapse and extrasynaptic sites during maturation, and the conductance level exhibited by a given receptor ma cromolecule may reflect the stochiometry of subunit composition.