MOTOR DISCOORDINATION RESULTS FROM COMBINED GENE DISRUPTION OF THE NMDA RECEPTOR NR2A AND NR2C SUBUNITS, BUT NOT FROM SINGLE DISRUPTION OF THE NR2A OR NR2C SUBUNIT

NMDA receptors consist of two distinct classes of subunits. The NR1 su bunit possesses all properties of the NMDA receptor-channel complex, w hereas four NR2 subunits (NR2A-2D) potentiate and differentiate NMDA r eceptor responses by heteromeric assemblies with NR1. The mRNAs for th e five NMDA receptor subunits are expressed in the cerebellum in a dis tinct temporospatial manner. To study functions of the NMDA receptors in the cerebellum, we generated knockout mice deficient in either NR2A or NR2C or both of these subunits. All three mutant mice developed no rmally and showed normal overall morphology of the cerebellum. The NMD A receptor-mediated components of EPSCs in granule cells, as assessed by whole-cell recordings of cerebellar slices, were reduced in NR2A- a nd NR2C-deficient mice and nearly abolished in mice lacking both NR2A and NR2C. The NR2A- and NR2C-deficient granule cells were different in the current-voltage relationship and time course of NMDA receptor res ponses. The NR2A and NR2C subunits thus contribute to distinct NMDA re ceptor-mediated excitatory transmission in messy fiber-granule cell sy napses in the mature cerebellum, Both NR2A- and NR2C-deficient mice sh owed no impaired movements in the motor coordination tasks tested. The mutant mice deficient in both NR2A and NR2C could also manage simple coordinated tasks, such as staying on a stationary or a slowly rotatin g rod, but failed more challenging tasks such as staying on a quickly rotating rod. These data demonstrate that the NMDA receptors play an a ctive role in motor coordination.