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

Abstract

NMDA receptors consist of two distinct classes of subunits. The NR1 subunit possesses all properties of the NMDA receptor-channel complex, whereas four NR2 subunits (NR2A-2D) potentiate and differentiate NMDA receptor responses by heteromeric assemblies with NR1. The mRNAs for the five NMDA receptor subunits are expressed in the cerebellum in a distinct 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 normally and showed normal overall morphology of the cerebellum. The NMDA receptor-mediated components of EPSCs in granule cells, as assessed by whole-cell recordings of cerebellar slices, were reduced in NR2A- and 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 responses. The NR2A and NR2C subunits thus contribute to distinct NMDA receptor-mediated excitatory transmission in mossy fiber- granule cell synapses in the mature cerebellum. Both NR2A-and NR2C-deficient mice showed 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 rotating rod, but failed more challenging tasks such as staying on a quickly rotating rod. These data demonstrate that the NMDA receptors play an active role in motor coordination.