| Co-Investigator(Kenkyū-buntansha) |
SAKATA-HAGA Hiromi University of Tokushima, School of Medicine Department of Anatomy and Developmental Neurobiology, Assistant professor, 医学部, 助手 (50294666)
SAWADA Kazuhiko University of Tokushima, School of Medicine Department of Anatomy and Developmental Neurobiology, Associate professor, 医学部, 助教授 (10284324)
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| Research Abstract |
Rolling mouse Nagoya (RMN) is an ataxic mutant that carries a mutation in a gene encoding for P/Q-type Ca^<2+> channel α_<1A> subunit. In humans, defects in this gene are responsible for Ca^<2+> channelopathy such as familial hemiplegic migraine and episodic ataxia type-2. Corticotropin-releasing factor (CRF) is widely localized throughout the central nervous system. In the cerebellum, CRF has been found in subsets of climbing and mossy fibers, and plays a role in increasing sensitivity of cerebellar cortical neurons to glutamate, This study aimed to clarify the involvement of CRF-positive cerebellar afferent fibers in the development of ataxic symptoms of RMN
In RMN, CRF immunostaining in some climbing and mossy fibers was much more intense, but the distribution of these fibers remained the same as in non-ataxic littermates (control mice). Double immunostaining for CRF and tyrosine hydroxylase (TH) revealed that TH immunostaining abnormally appeared in some Purkinje cells receiving CRF
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-positive climbing fibers. By semi-quantitative in situ hybridization, the level of CRF mRNA signals increased in some original neurons of the climbing fibers of RMN. Signal levels in the β-nucleus and ventrolateral protrusion of inferior olive (ION) were about two-fold higher in RMN than in the controls. Signal levels in the dorsal nucleus, principal nucleus and subnucleus A of the ION were slightly but significantly higher in RMN than in the controls. In the vestibulocerebellum, the number of CRF-positive mossy fibers was much more in RMN than in the controls. Double immunofluorecence for CRF and calretinin in revealed that some CRF-positive mossy fibers closely opposed to calretinin-positive unipolar brush cells, which play roles in amplifying excitatory inputs from vestibulocerebellar mossy fibers
These results suggest that increased level of CRF in the particular subsets of climbing and mossy fibers alters excitability of cerebellar cortical neurons, involved in the ataxic symptoms of RMN Less
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