Genetic analysis of factors associated with synaptic morphology and function in the cerebellum

The cerebellum is the center for motor coordination. Abnormal synaptic morphology and function in the cerebellum often causes human diseases with ataxia. To characterize the role of novel genes critical for proper synaptic structure and function in the cerebellum, we studied two ataxic mouse mutants--- nur17 and Carwdl.;nur17 mice exhibit both coat color dilution and ataxia which are phenotypes indicative of skin and cerebellar abnormalities. Further phenotypic analysis found that nur17 mice display common characteristics of neurodegenerative disorders such as abnormal protein accumulation, ER-stress and neurofibrillary tangles in the cerebellum that may be the direct causes of extensive Purkinje cell loss in nur17 mice. We identified the underlying nur17 mutation (T-C) in archain 1 (Arcn1) which encodes a subunit of the coat protein I (COPI) complex that is required for ER-Golgi protein trafficking. Consistent with studies in yeast mutant of delta-COP (yeast orholog of Arcn1), we found that ER-Golgi protein trafficking is disrupted in nur17 mice. Our study is the first demonstration that ARCN1 plays a conserved important role in ER-Golgi protein trafficking in the mammalian system, and a direct association between the COPI coatomer complex and neurodegeneration.;We characterized another ataxic mouse mutant carrying a mutation in Car8. Electrophysiological analysis suggested functional synapses have normal release probability but the number of functional synapses is lower in mutants. Histological study revealed that the climbing fibers extended abnormally to the distal PC dendrites and numerous PC dendritic spines failed to form synapses primarily in distal dendrites and occasionally multiple spines contact a single varicosity. These abnormalities of parallel fiber-PC synapses may cause the defects in excitatory transmission. Taken together, our work demonstrated that Car8 plays a critical role in synaptogenesis and/or maintenance of proper synaptic structure and function in the cerebellum.;In conclusion, mouse genetics combined with biochemical and molecular approaches is a powerful strategy to identify novels genes of interest and to reveal the fundamental mechanisms of biological processes such as protein trafficking and synaptogenesis. Because many genes and molecular pathways are highly conserved between mouse and human, information obtained from studies on mouse has direct implications to human.