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). During postnatal development, a single CF is selectively strengthened in each PC and becomes a “winner” CF that is presumed to remain into adulthood, whereas the other “loser” CFs are eliminated. These developmental changes are dependent on neural activity and signal cascades in postsynaptic PCs. Several molecules essential for CF synapse elimination have been identified in postsynaptic PCs. Importantly, we have recently uncovered that Semaphorin3A (Sema3A) and Semaphorin7A (Sema7A) derived from postsynaptic PCs act retrogradely onto presynaptic CFs and regulate CF synapse elimination. We demonstrate that Sema3A strengthens and maintains CF synapses from postnatal day 8 (P8) to P18 and opposes the force of CF elimination. In contrast, Sema7A facilitates elimination of weaker CFs from PC somata after P15. In the continuing studies, we searched for molecules that mediate these retrograde semaphorin signals in presynaptic CFs. This short article describes how Sema3A strengthens and maintains, whereas Sema7A promotes elimination of CF synapses through respective receptors and downstream molecules in presynaptic CFs during postnatal cerebellar development.
Climbing fiber Purkinje cell Synapse elimination Retrograde signal Semaphorin
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We thank K. Matsuyama, M. Sekiguchi, and M. Baba for the technical assistance. This work was supported by Grants-in-Aid for Scientific Research (15H05568 to N.U., 25000015 to M.K.) from JSPS, Japan, and by Brain/MINDS from MEXT and AMED, Japan and SRPBS from AMED, Japan.
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Conflict of Interest
The authors declare that there are no conflicts of interest in the submission of this manuscript to The Cerebellum.
Watanabe M, Kano M. Climbing fiber synapse elimination in cerebellar Purkinje cells. Eur J Neurosci. 2011;34(10):1697–710.CrossRefPubMedGoogle Scholar
Hashimoto K, Ichikawa R, Kitamura K, Watanabe M, Kano M. Translocation of a “winner” climbing fiber to the Purkinje cell dendrite and subsequent elimination of “losers” from the soma in developing cerebellum. Neuron. 2009;63(1):106–18.CrossRefPubMedGoogle Scholar
Bosman LW, Konnerth A. Activity-dependent plasticity of developing climbing fiber-Purkinje cell synapses. Neuroscience. 2009;162(3):612–23.CrossRefPubMedGoogle Scholar
Hashimoto K, Kano M. Postnatal development and synapse elimination of climbing fiber to Purkinje cell projection in the cerebellum. Neurosci Res. 2005;53(3):221–8.CrossRefPubMedGoogle Scholar
Hashimoto K, et al. Postsynaptic P/Q-type Ca2+ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum. Proc Natl Acad Sci U S A. 2011;108(24):9987–92.CrossRefPubMedPubMedCentralGoogle Scholar
Miyazaki T, Hashimoto K, Shin HS, Kano M, Watanabe M. P/Q-type Ca2+ channel α1A regulates synaptic competition on developing cerebellar Purkinje cells. J Neurosci. 2004;24(7):1734–43.CrossRefPubMedGoogle Scholar
Ichise T, et al. mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science. 2000;288(5472):1832–5.CrossRefPubMedGoogle Scholar
Kano M, et al. Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron. 1997;18(1):71–9.CrossRefPubMedGoogle Scholar
Levenes C, Daniel H, Jaillard D, Conquet F, Crepel F. Incomplete regression of multiple climbing fibre innervation of cerebellar Purkinje cells in mGluR1 mutant mice. Neuroreport. 1997;8(2):571–4.Google Scholar
Uesaka N, et al. Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science. 2014;344(6187):1020–3.CrossRefPubMedGoogle Scholar
Hashimoto K, Kano M. Synapse elimination in the developing cerebellum. Cellular and molecular life sciences. 2013;70(24):4667–80.Google Scholar
Pasterkamp RJ. Getting neural circuits into shape with semaphorins. Nature reviews. Neuroscience. 2012;13(9):605–18.PubMedGoogle Scholar
Scott GA, McClelland LA, Fricke AF, Fender A. Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression. The Journal of investigative dermatology. 2009;129(4):954–63.CrossRefPubMedGoogle Scholar