Abstract
Neurons form exuberant synapses with target cells early in development. Then, necessary synapses are selectively strengthened whereas unnecessary connections are weakened and eventually eliminated during postnatal development. This process is known as synapse elimination and is a crucial step for shaping immature neural circuits into functionally mature versions. Accumulating evidence suggests that retrograde signaling from postsynaptic cells regulates synapse elimination, but the underlying mechanisms remain unknown. Here, we show that semaphorin3A (Sema3A) and semaphorin7A (Sema7A) mediate retrograde signals for elimination of redundant climbing fiber (CF) to Purkinje cell (PC) synapses in the developing cerebellum, a representative model of synapse elimination in the central nervous system. We picked up candidate retrograde signaling molecules that are expressed in PCs during the period of CF synapse elimination and the receptors of these candidate molecules that are present in CFs. We then assessed the effects of lentivirus-mediated RNAi-knockdown of these molecules on CF synapse elimination. By this systematic screening, we found that knockdown of Sema3A in PCs or its co-receptor, plexinA4 (PlxnA4), in CFs accelerated CF synapse elimination and decreased CF-mediated synaptic inputs. Conversely, knockdown of Sema7A in PCs or either of the two receptors for Sema7A, plexinC1 (PlxnC1) and integrinB1 (ItgB1), in CFs impaired CF synapse elimination. Importantly, the effect of Sema7A involves signaling by type 1 metabotropic glutamate receptor (mGluR1), a canonical pathway in PCs for the final stage of CF synapse elimination. These results demonstrate that specific semaphorins act as retrograde signaling molecules and regulate distinct processes of CF synapse elimination during postnatal cerebellar development.
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Acknowledgments
The authors thank A. Nienhuis, St. Jude Children’s Research Hospital and George Washington University for the gifts of the lentiviral backbone vector and the packaging plasmid; K. Kitamura and K. Hashimoto for helpful discussions; and K. Matsuyama, M. Sekiguchi, S. Tanaka, and A. Koseki for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (19100005 to M.W. 21220006 and 25000015 to M.K. and 23650160 to N.U.), the Funding Program for Next Generation World-Leading Researchers (LS021) to H.H., the Strategic Research Program for Brain Sciences (Development of biomarker candidates for social behavior), and the Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) from MEXT, Japan.
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The authors declare that there are no conflicts of interest in the submission of this manuscript to The Cerebellum.
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Uesaka, N., Uchigashima, M., Mikuni, T. et al. Retrograde Signaling for Climbing Fiber Synapse Elimination. Cerebellum 14, 4–7 (2015). https://doi.org/10.1007/s12311-014-0615-y
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DOI: https://doi.org/10.1007/s12311-014-0615-y