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Plasticity of the developmentally arrested staggerer cerebellum in response to exogenous RORα

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Abstract

Retinoid-related orphan receptor α (RORα) is a critical master transcription factor that governs postnatal cerebellar development. An RORα-deficient cerebellum has a persistent external granular layer (EGL), rudimentary Purkinje cell (PC) dendrites, grossly reduced numbers of immature parallel fiber (PF)-PC synapses, and multiple climbing fibers (CF) innervating PCs in mice after 3 weeks of age when these features have disappeared in wild-type mice. Functionally, metabotropic glutamate receptor (mGluR)-mediated signaling in PCs is completely abrogated. Here we examined whether these defects could be corrected by lentivirally providing the RORα gene to 3-week-old PCs of RORα-deficient homozygous staggerer (sg/sg) mice. RORα expression in sg/sg PCs significantly increased the numbers of PF–PC synapses, spines on PC dendritic branchlets, and internal granule cells, concomitant with regression of the EGL, suggesting enhanced proliferation in the EGL and migration of post-mitotic progeny into the internal granular layer with augmented synaptogenesis between PFs and PC dendrites. However, the primary dendritic stems were only slightly extended, and mGluR signaling and the loss of redundant CF synapses in sg/sg PCs remained unrestored. These results suggest that the mitogenic and migratory potential of external granule cells in response to RORα was preserved in the >3-week-old sg/sg mouse cerebellum. Moreover, sg/sg PCs sprouted spines and formed synapses with PFs. However, lengthening of the primary dendritic stems, establishment of mGluR signaling, and removal of CF synapses in sg/sg PCs were regressed by 3 weeks of age.

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Acknowledgments

We are indebted to Dr. Nobutake Hosoi for many helpful discussions. We thank Junko Sugiyama, Asako Onishi, and Hiromi Hirai for maintaining and genotyping the mutant mice. This study was supported by a grant from the Funding Program for Next Generation World-Leading Researchers (LS021), grants from Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare and and Gunma University Initiative for Advanced Research (GIAR) (to H. Hirai), a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS), and a Grant-in-Aid for Young Scientists (B) KAKENHI (22700374).

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  1. Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan

    Akira Iizuka, Yasunori Matsuzaki, Ayumu Konno & Hirokazu Hirai

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  1. Akira Iizuka
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  2. Yasunori Matsuzaki
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  3. Ayumu Konno
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  4. Hirokazu Hirai
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Correspondence to Hirokazu Hirai.

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Iizuka, A., Matsuzaki, Y., Konno, A. et al. Plasticity of the developmentally arrested staggerer cerebellum in response to exogenous RORα. Brain Struct Funct 221, 2879–2889 (2016). https://doi.org/10.1007/s00429-015-1077-9

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