Critical period for activity-dependent synapse elimination in developing cerebellum

Synapse elimination is considered to be the final step in neural circuit fo rmation, by causing refinement of redundant connections formed at earlier d evelopmental stages. The developmental loss of climbing fiber innervation f rom cerebellar Purkinje cells is an example of such synapse elimination. It has been suggested that NMDA receptors are involved in the elimination of climbing fiber synapses. In the present study, we probed the NMDA receptor- dependent period of climbing fiber synapse elimination by using daily intra peritoneal injections of the NMDA receptor antagonist MK-801. We found that blockade of NMDA receptors during postnatal day 15 (P15) and P16, but not before or after this period, resulted in a higher incidence of multiple cli mbing fiber innervation and caused a mild but persistent loss of motor coor dination. Neither basic synaptic functions nor cerebellar morphology were a ffected by this manipulation. Chronic local application of MK-801 to the ce rebellum during P15 and P16 also yielded a higher incidence of multiple cli mbing fiber innervation. During P15-P16, large NMDA receptor-mediated EPSCs were detected at the mossy fiber-granule cell synapse, but not at the para llel fiber-Purkinje cell or climbing fiber-Purkinje cell synapse. It is the refore likely that the NMDA receptors located at the mossy fiber-granule ce ll synapse mediate signals leading to the elimination of surplus climbing f ibers. These results suggest that an NMDA receptor-dependent phase of climb ing fiber synapse elimination lasts 2 d at most. During this phase, the fin al refinement of climbing fiber synapses occurs, and disruption of this pro cess leads to permanent impairment of cerebellar function.