Synapse elimination in the developing cerebellum

Kouichi Hashimoto,Masanobu Kano

doi:10.1007/s00018-013-1405-2

Abstract

Neural circuits in neonatal animals contain numerous redundant synapses that are functionally immature. During the postnatal period, unnecessary synapses are eliminated while functionally important synapses become stronger and mature. The climbing fiber (CF) to the Purkinje cell (PC) synapse is a representative model for the analysis of postnatal refinement of neuronal circuits in the central nervous system. PCs are initially innervated by multiple CFs with similar strengths around postnatal day 3 (P3). Only a single CF is selectively strengthened during P3–P7 (functional differentiation), and the strengthened CF undergoes translocation from soma to dendrites of PCs from P9 on (dendritic translocation). Following the functional differentiation, supernumerary CF synapses on the soma are eliminated, which proceeds in two distinct phases: the early phase from P7 to around P11 and the late phase from around P12 to P17. Here, we review our current understanding of cellular and molecular mechanisms of CF synapse elimination in the developing cerebellum.

Highlights

Formation of precise neuronal connections during development is a prerequisite for proper functions of the nervous system
The somatic multiple climbing fiber (CF) innervation observed in global GluD2 KO mice [80] was not induced by the deletion of GluD2 in adult mice [88]. This evidence suggests that the persistent somatic CF innervation is the consequence of impaired late-phase of CF elimination. These results indicate that parallel fiber (PF) play two distinct roles in establishing CF innervation of Purkinje cell (PC): (1) PFs restrict the sites of CF innervation to proximal dendrites of PCs; this function is seen during postnatal development and in adulthood; and (2) PFs drive the late-phase of CF elimination by removing somatic CF synapses during postnatal development [88]
It is most likely that chronic NMDA receptor blockade in the cerebellum impairs the late phase CF elimination by suppressing the activation of NMDA receptors at mossy fibers (MF)-granule cell (GC) synapses [102]. These results strongly suggest that mGluR1 is activated at PF-PC synapses by neural activity along the MF-GC-PF pathway and plays a pivotal role in the late phase of CF elimination [102]

Summary

Introduction

Formation of precise neuronal connections during development is a prerequisite for proper functions of the nervous system. CF synapse elimination does not proceed in parallel with functional differentiation of multiple CFs, but starts after the strengthening of single CFs in individual PCs. As we mentioned, surplus CF elimination proceeds in at least two distinct phases: the early and the late phase of CF elimination. Assuming that the developmental course of CF synapse elimination is similar between rats and mice, this result suggests that the abnormal over-synchronized activation of CFs during the early phase impairs synapse elimination.

Results

Conclusion