Cerebellar Abnormalities Based on Chemical Neuroanatomy in Cav2.1 Mutant, Rolling Mouse Nagoya

This review summarizes cerebellar abnormalities based on chemical neuroanatomy in the ataxic mutant, rolling mouse Nagoya. This mutant mouse carries a mutation in the gene encoding for the α1A subunit of the voltage-gated P/Q-type Ca channel (Cav2.1), as do tottering, leaner, rocker and wobbly mice, and is a useful model for human neurological diseases such as episodic ataxia type-2 and familial hemiplegic migraine. Whereas no obvious cerebellar deformations are detected in rolling mice, the altered functions of cerebellar cortical neurons can be revealed as expressional changes in molecules related to the regulation of intracellular Ca. The non-enzymatically active form of tyrosine hydroxylase (TH) was ectopically expressed in zebrin II-positive/heat shock protein 25-negative Purkinje cell population. Although types 1, 2 and 3 ryanodine receptors (RyR1, RyR2 and RyR3) were uniformly expressed in cerebellar Purkinje and/or granular cells in wild-type mice, the rolling cerebellum uniformly exhibited a reduced RyR1 expression in Purkinje cells and a slight enhancement of RyR3 expression in granular cells. An increased Cav2.1 channel expression was also revealed in the deep cerebellar nuclei of rolling mice. On the other hand, increased levels of neurotransmitters/neuromodulators in cerebellar afferents were noted. Corticotropin-releasing factor (CRF) immunostaining in climbing and mossy fiber subsets was more intense in the rolling cerebellum than in the wild-type mouse cerebellum without changes in the overall distribution. Serotonin immunostaining was also increased in serotonergic fiber terminals in the vermis of rolling mice. Thus, cerebellar abnormalities have been identified in rolling mice by chemical neuroanatomical techniques. Such neurochemical modulation of the cerebellar cortex may well be the key to understanding the pathogenesis of cerebellar ataxia of Ca channelopathy.