Abstract
Elimination of early-formed redundant synapses during postnatal development is essential for functional neural circuit formation. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs). A single CF is strengthened whereas the other CFs are eliminated in each PC dependent on postsynaptic activity in PC, but the underlying mechanisms are largely unknown. Here, we report that brain-derived neurotrophic factor (BDNF) from PC facilitates CF synapse elimination. By PC-specific deletion of BDNF combined with knockdown of BDNF receptors in CF, we show that BDNF acts retrogradely on TrkB in CFs, and facilitates elimination of CF synapses from PC somata during the third postnatal week. We also show that BDNF shares signaling pathway with metabotropic glutamate receptor 1, a key molecule that triggers a canonical pathway for CF synapse elimination. These results indicate that unlike other synapses, BDNF mediates punishment signal for synapse elimination in the developing cerebellum.
Highlights
Elimination of early-formed redundant synapses during postnatal development is essential for functional neural circuit formation
The expression of another putative brain-derived neurotrophic factor (BDNF) receptor, SORT138, increased only slightly from P7 to P15 (Supplementary Fig. 1d). These results show that BDNF and its receptors are abundantly expressed in the cerebellum at least after P15
We found no significant differences in the excitatory postsynaptic currents (EPSCs) parameters for climbing fibers (CFs)-mono, CF-multi-S and CF-multi-W (Supplementary Table 3), total CF-EPSC amplitude, disparity ratio or index (Supplementary Table 4) between control and BDNF-KD Purkinje cells (PCs), indicating normal strengthening of single “winner” CFs and their dendritic translocation
Summary
Elimination of early-formed redundant synapses during postnatal development is essential for functional neural circuit formation. Neuronal connections are diverse and redundant around birth, but they are refined during postnatal development by selective strengthening of necessary synapses and elimination of unnecessary redundant connections in activity-dependent manners[1,2,3] This process, known as synapse elimination, is widely thought to be crucial for shaping immature neural circuits into functionally mature versions. In TrkB knockout mice, PCs are reported to be innervated by multiple CFs at P1432 and at P20–P2432, 33, indicating that BDNF signaling is involved in CF synapse elimination in the cerebellum. We show that BDNF and mGlu[1] function presumably along the same signaling pathway for CF synapse elimination These results strongly suggest that retrograde BDNF to TrkB signaling regulated by mGlu[1] is required for the late phase of CF synapse elimination in the developing cerebellum
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