Synapse elimination in the central nervous system

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Functional neural circuit formation during postnatal development involves the elimination of early-formed redundant synapses. In the neonatal mouse cerebellum, each Purkinje cell is innervated by multiple climbing fibers (CFs). Their synaptic strengths are initially uniform but one CF strengthens relative to other CFs during the first postnatal week. Then the weaker CFs are eliminated during the second postnatal week. Projections from the retina to the lateral geniculate nucleus (LGN) undergo similar developmental changes, that is the elimination of the majority of inputs and strengthening of a few afferents that remain. Recent studies have clarified that in both cerebellum and LGN, synapse refinement consists of multiple phases and that distinct types of neural activity drive synaptic remodeling in each developmental phase.

Introduction

Synapse elimination is considered to be a fundamental process for the developmental refinement of neural circuits [1, 2, 3]. Synapse elimination has been studied extensively in the neuromuscular junction and autonomic ganglia. In these peripheral systems, synapses are large and can be visualized by labeling axons and/or postsynaptic structures, which allow us to monitor the changes over days and weeks by time-lapse imaging technique [4, 5]. However, it is difficult to do such detailed analyses in the central nervous system (CNS), because of small size of synapse, heterogeneity and abundance of synaptic inputs to each neuron, and the complexity of synaptic organization.

In this respect, climbing fiber (CF) to Purkinje cell (PC) synapse in the cerebellum has been an excellent model to study synapse elimination in the developing CNS [6, 7]. PCs in the adult cerebellum receive two major excitatory inputs, namely parallel fibers (PFs) and CFs [8]. PFs are bifurcated axons of cerebellar granule cells (GCs) and form synapses on spines of PC's distal dendrites. Each synaptic input is weak but as many as 100 000 PFs make contacts on dendritic spines of a single PC [8]. In contrast, the majority of PCs in the adult cerebellum are innervated by single CFs (mono-innervation) but each CF makes strong synaptic contacts on PC's proximal dendrites [8]. In early postnatal days, however, all PCs are innervated by multiple CFs (multiple innervation) [6, 7]. These surplus CFs are eliminated eventually and mono-innervation is attained by the end of the third postnatal week in mice [9, 10, 11, 12]. Besides CF to PC synapses in the cerebellum, synapses in the sensory thalamus are known to undergo synapse elimination during postnatal development. In the lateral geniculate nucleus (LGN), axons of retinal ganglion cells (RGCs) segregate into eye-specific regions before eye opening [13]. This initial circuit formation is dependent on spontaneous activity of RGCs and molecular signals [14, 15, 16, 17, 18]. In mice, just before eye opening around postnatal day 12 (P12), each LGN neuron receives synaptic inputs from as many as 20 RGCs [19]. Two weeks after eye opening, only one to three RGC axons innervate each LGN neuron but the remaining synaptic inputs are about 50-fold stronger than those before eye opening [19]. Similar synaptic reorganizations have been reported to occur in the ventral basal thalamus that relays somatosensory information to the cortex [20], and the endbulb synapses of the chick cochlear nucleus [21].

In this review article, we describe synapse elimination at CF to PC synapses in the cerebellum and synapses between RGC axons and LGN relay neurons (retinogeniculate synapses), and discuss how neural activity influences neural circuit remodeling.

Section snippets

Three phases of CF synapse elimination

Earlier studies have revealed that the presence of intact GCs and normal formation of PF to PC synapses are prerequisite for CF synapse elimination. For example, multiple CF innervation persists into adulthood in rodents that have undergone X-irradiation after birth, which kills proliferating GCs and causes ‘hypogranular’ cerebella [6]. Furthermore, CF synapse elimination is impaired in null mutant mice of glutamate receptor δ2 subunit (GluRδ2) [22, 23], a PC-specific molecule crucial for the

Spontaneous activity around the time of eye opening is essential for the refinement of retinogeniculate synapses

Morphological studies demonstrate that significant rearrangement of RGC axon arbors occurs after initial connections are formed [51]. In adult animals, LGN neurons receive sensory inputs from very few RGCs. An electrophysiological analysis on acute mouse LGN slices has revealed that each LGN relay neuron receives more than 20 inputs well after eye-specific zones are formed [19]. All but a few inputs are eliminated over a three-week period spanning eye opening [19]. In parallel, remaining inputs

Conclusions

Postnatal development of CF synapses in the cerebellum is now thought to consist of three distinct phases [32]. First, functional differentiation of multiple CFs into one strong and a few weak inputs that occurs from P3 to P7. Second, the ‘early phase’ of CF synapse elimination from P7 to around P12. Third, the ‘late phase’ of CF synapse elimination from around P12 (Figure 1). The functional differentiation depends largely on competition among multiple CFs, which seems to be mediated by

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Madoka Narushima and Mariko Miyata for helpful suggestions. This work was supported by Grants-in-Aid for Scientific Research (17023021 and 17100004 to MK) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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