Critical Period for Activity-Dependent Synapse Elimination in Developing Cerebellum

Abstract

Synapse elimination is considered to be the final step in neural circuit formation, by causing refinement of redundant connections formed at earlier developmental stages. The developmental loss of climbing fiber innervation from 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 intraperitoneal 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 climbing fiber innervation and caused a mild but persistent loss of motor coordination. Neither basic synaptic functions nor cerebellar morphology were affected by this manipulation. Chronic local application of MK-801 to the cerebellum during P15 and P16 also yielded a higher incidence of multiple climbing fiber innervation. During P15-P16, large NMDA receptor-mediated EPSCs were detected at the mossy fiber-granule cell synapse, but not at the parallel fiber-Purkinje cell or climbing fiber-Purkinje cell synapse. It is therefore likely that the NMDA receptors located at the mossy fiber-granule cell synapse mediate signals leading to the elimination of surplus climbing fibers. These results suggest that an NMDA receptor-dependent phase of climbing fiber synapse elimination lasts 2 d at most. During this phase, the final refinement of climbing fiber synapses occurs, and disruption of this process leads to permanent impairment of cerebellar function.

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

“…This could be correlated to the fact that mGluR1 can readily be activated by parallel fibre inputs (Finch & Augustine 1998;Takechi et al 1998) but hardly by climbing fibre inputs without blockade of glutamate transporters (Dzubay & Otis 2002). Furthermore, we demonstrate that chronic blockade of NMDA receptors within the cerebellum specifically impairs the late phase of climbing fibre synapse elimination (Kakizawa et al 2000). Because NMDA receptors are not present at excitatory synapses of Purkinje cells but are abundantly expressed at mossy fibre to granule cell synapses, the chronic blockade of NMDA receptors within the cerebellum should affect mossy fibre to granule cell transmission.…”

“…Because NMDA receptors are not present at excitatory synapses of Purkinje cells but are abundantly expressed at mossy fibre to granule cell synapses, the chronic blockade of NMDA receptors within the cerebellum should affect mossy fibre to granule cell transmission. These results suggest that neural activity along mossy fibre (granule cell) and parallel fibre (Purkinje cell) pathway, and subsequent activation of mGluR1 is a prerequisite for the late phase of climbing fibre synapse elimination (Kakizawa et al 2000). Figure 3 illustrates the current model for mechanisms underlying the late phase of climbing fibre synapse elimination.…”

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

“…Recently, it has been reported that the late phase of cf elimination was impaired in PC-selective γ-2 KO mice, with the absolute strengths of cf inputs scaled down and cf-induced Ca 2+ transients significantly reduced (25). Because excitatory synaptic transmission to PCs is primarily mediated by AMPARs after the third postnatal week (28,29), the smaller amplitude of AMPARmediated EPSCs, and reduced activation of P/Q-type voltagedependent calcium channels, resulted in multiple cf innervation of PCs (25). We have not examined whether synapse elimination is impaired in our γ-2 PC KO mutant, but this recent data suggest that our γ-2 PC KO; γ-7 WT and γ-2 PC KO; γ-7 KO mutants likely exhibit multiple cf innervation, although we included responses in our study that were all or none.…”

H2-K b and H2-D b regulate cerebellar long-term depression and limit motor learning

“…Neural activity during development is required for normal elimination of supernumerary climbing fiber (CF) axons (14,15). Given the observation that MHCI transcripts are detected in PCs by postnatal d 7 ( Fig.…”