Regulation of tyrosine hydroxylase expression in tottering mouse Purkinje cells

Tottering (tg) mice inherit a missense mutation in the Alpha1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in tottering mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in tottering mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in tottering mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in tottering mouse Purkinje cells is regulated by Purkinje cell excitability.