IMPAIRED CEREBELLAR SYNAPTIC PLASTICITY AND MOTOR-PERFORMANCE IN MICELACKING THE MGLUR4 SUBTYPE OF METABOTROPIC GLUTAMATE-RECEPTOR

The application of the glutamate analog L-2-amino-4-phosphonobutyric a cid (L-AP4) to neurons produces a suppression of synaptic transmission . Although L-AP4 is a selective ligand at a subset of metabotropic glu tamate receptors (mGluRs), the precise physiological role of the L-AP4 -activated mGluRs remains primarily unknown, To provide a better under standing of the function of L-AP4 receptors, we have generated and stu died knockout (KO) mice lacking the mGluR4 subtype of mGluR that displ ays high affinity for L-AP4, The mGluR4 mutant mice displayed normal s pontaneous motor activity and were unimpaired on the bar cross test, i ndicating that disruption of the mGluR4 gene did not cause gross motor abnormalities, impairments of novelty-induced exploratory behaviors, or alterations in fine motor coordination. However,the mutant mice wer e deficient on the rotating rod motor-learning test, suggesting that m GluR4 KO mice may have an impaired ability to learn complex motor task s. Patch-clamp and extracellular field recordings from Purkinje cells in cerebellar slices demonstrated that L-AP4 had no effect on synaptic responses in the mutant mice, whereas in the wild-type mice 100 mu M L-AP4 produced a 23% depression of synaptic responses with an EC(50) o f 2.5 mu M An analysis of presynaptic short-term synaptic plasticity a t the parallel fiber-->Purkinje cell synapse demonstrated that paired- pulse facilitation and post-tetanic potentiation were impaired in the mutant mice. In contrast, long-term depression (LTD) was not impaired. These results indicate that an important function of mGluR4 is to pro vide a presynaptic mechanism for maintaining synaptic efficacy during repetitive activation. The data also suggest that the presence of mGlu R4 at the parallel fiber-->Purkinje cell synapse is required for maint aining normal motor function.