Fureman Brandy E, Campbell Daniel B, Hess Ellen J
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Neurotox Res. 2003;5(7):521-8. doi: 10.1007/BF03033162.
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.
蹒跚（tg）小鼠继承了P/Q型钙通道α1A亚基的错义突变。这种突变导致小脑L型钙通道密度增加，并在一部分小脑浦肯野细胞中异常调节酪氨酸羟化酶（TH）基因表达，而浦肯野细胞通常不表达TH。行为表型包括运动障碍发作，可被L型钙通道拮抗剂阻断。为了检验小脑TH mRNA表达可在体内通过L型钙通道阻滞进行调控的假说，对对照小鼠和蹒跚小鼠长期给予L型钙通道拮抗剂尼莫地平。长期尼莫地平治疗显著降低了蹒跚小鼠浦肯野细胞中TH mRNA的表达。在未改变蹒跚小鼠小脑L型钙通道密度增加的情况下观察到了这种效应。长期尼莫地平治疗对蹒跚小鼠儿茶酚胺能神经元（包括蓝斑和黑质的神经元）中的TH mRNA表达没有影响。然而，药物治疗后观察到对照小鼠黑质中TH mRNA表达略有降低。这些数据表明，蹒跚小鼠浦肯野细胞中TH的异常表达受浦肯野细胞兴奋性的调节。
