title: Stargazin mutation impairs cerebellar synaptogenesis, synaptic maturation and synaptic protein distribution.
abstract: Stargazin mutation results in absence epilepsy and cerebellar ataxia in stargazer (stg) mice. We have previously discovered defects of AMPA receptor function, failure of BDNF expression and immature morphology specifically in the cerebellar cortex of stg mice. To further characterize the nature of synaptic abnormalities, we examined the ultrastructure of cerebellar granule cell output synapses and measured the expression levels of several synaptic proteins in different brain regions of stg mutant. Electron microscopic examination revealed a number of immature features in the molecular layer of the mutant cerebellar cortex, including the presence of desmosoid plaques, concentric profiles of parallel fibers, smaller presynaptic terminal and fewer synaptic vesicles. Quantitative measurement showed a significantly lower number of synapses and smaller area of presynaptic terminals in adult stg cerebellum when compared with age-matched wildtype. Immunoblotting analysis of the SNARE proteins revealed selective reduction of the levels of synaptobrevin and synaptophysin in synaptosomes from stg cerebellum. The expression levels of synapsins were not altered in stg cerebellum, but showed a significant upregulation in stg cerebral cortex and hippocampus. Our results suggest that, despite the relatively normal gross morphology of cerebellum, stargazin mutation results in abnormal ultrastructure of cerebellar synapses, and stargazin-induced regional failure of BDNF expression may be responsible for abnormal SNARE protein distribution and partially attributes to the defects in the synaptic ultrastructure.
authors.affiliation: Department of Ophthalmology, Pharmacology and Neuroscience, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hongdi
authors.initials: H
authors.lastname: Meng
authors.forename: Nicole
authors.initials: N
authors.lastname: Walker
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Qiao
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D015220:Calcium Channels / Q000235:genetics*; D002531:Cerebellum / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000502:physiology*; D050683:R-SNARE Proteins / Q000378:metabolism; D050600:SNARE Proteins / Q000378:metabolism; D013569:Synapses / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology* / Q000648:ultrastructure; D016704:Synapsins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
chemical_list: C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D050683:R-SNARE Proteins; D050600:SNARE Proteins; D016704:Synapsins; D016708:Synaptophysin