Alonso Isabel, Marques Joana M, Sousa Nuno, Sequeiros Jorge, Olsson I Anna S, Silveira Isabel
UnIGENe, IBMC, Universidade do Porto, Portugal; ICBAS, Universidade do Porto, Portugal.
Neurobiol Aging. 2008 Nov;29(11):1733-43. doi: 10.1016/j.neurobiolaging.2007.04.005. Epub 2007 May 21.
The leaner mutation in mice affects the Ca(v)2.1 voltage-gated calcium channel alpha(1A)-subunit gene (Cacna1a), causing a reduction in calcium currents predominantly in Purkinje cells. This reduction in calcium currents causes severe progressive cerebellar ataxia, beginning around postnatal day 10, in homozygous leaner mice (tg(la)/tg(la)), while their heterozygous littermates (tg(la)/+) present no obvious behavioral deficits. In humans, heterozygous mutations in the Cacna1a orthologous gene produce a broad range of neurological manifestations. To evaluate the phenotypic status of the tg(la)/+ animals, we assessed motor performance and cognition, at different ages, in these mutant mice. We were able to observe age-dependent impairment in motor and cognitive tasks; balance and motor learning deficits were found in demanding tasks on the rotarod and on the hanging wire test, while spatial learning and memory impairment was observed in the Morris water maze. Progressive dysfunction in escape reflexes, indicative of neurological impairment, was also present in tg(la)/+ animals. Although not presenting major motor alterations, tg(la)/+ mice show age-dependent motor and cognitive deficits.
小鼠中的“更瘦”突变影响Ca(v)2.1电压门控钙通道α(1A)亚基基因（Cacna1a），导致主要在浦肯野细胞中的钙电流减少。钙电流的这种减少在纯合子“更瘦”小鼠（tg(la)/tg(la)）中从出生后第10天左右开始引起严重的进行性小脑共济失调，而它们的杂合子同窝小鼠（tg(la)/+）没有明显的行为缺陷。在人类中，Cacna1a直系同源基因的杂合突变会产生广泛的神经学表现。为了评估tg(la)/+动物的表型状态，我们在这些突变小鼠的不同年龄评估了运动性能和认知能力。我们能够观察到运动和认知任务中与年龄相关的损伤；在转棒试验和悬线试验等要求较高的任务中发现了平衡和运动学习缺陷，而在莫里斯水迷宫中观察到了空间学习和记忆损伤。tg(la)/+动物中也存在逃避反射的进行性功能障碍，这表明存在神经损伤。尽管没有出现主要的运动改变，但tg(la)/+小鼠表现出与年龄相关的运动和认知缺陷。
