Roles of diverse glutamate receptors in brain functions elucidated by subunit-specific and region-specific gene targeting.

Glutamate receptor (GluR) channels play a major role in fast excitatory synaptic transmission in vertebrate central nervous system. We revealed the molecular diversity of the GluR channel by molecular cloning and investigated their physiological roles by subunit-specific gene targeting. NMDA receptor GluRepsilon1 KO mice showed increase in thresholds for hippocampal long-term potentiation and hippocampus-dependent contextual learning. The mutant mice performed delay eyeblink conditioning, but failed to learn trace eyeblink conditioning. GluRepsilon1 mutant suffered less brain injury after focal cerebral ischemia. NMDA receptor GluRepsilon2 KO mice showed impairment of the whisker-related neural pattern formation and suckling response, and died shortly after birth. Heterozygous (+/-) GluRepsilon2 mutant mice were viable and showed enhanced startle response to acoustic stimuli. GluRdelta2, a member of novel GluR channel subfamily we found by molecular cloning, is selectively expressed in the Purkinje cells of the cerebellum. GluRdelta2 KO mice showed impairments of cerebellar synaptic plasticity and synapse stability. GluRdelta2 KO mice exhibited impairment in delay eyeblink conditioning, but learned normally trace eyeblink conditioning. The phenotypes of NMDA receptor subunits and GluRdelta2 mutant mice suggest that diverse GluR subunits play differential roles in the brain functions.