University of Minnesota, Department of Neuroscience, Minneapolis, Minnesota.
J Neurophysiol. 2020 Oct 1;124(4):1183-1197. doi: 10.1152/jn.00100.2020. Epub 2020 Sep 9.
Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABA subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABA subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor. Purkinje cell specific knockout of the GABA subunit abolished all GABA-mediated inhibition in Purkinje cells, while leaving GABA-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABA from Purkinje cells did not produce deficits on the accelerating rotarod, nor did it result in decreased survival rates. However, a tremor phenotype was apparent, regardless of sex or background strain. This tremor mimicked the tremor seen in animals with a global knockout of the GABA subunit, and, like essential tremor in patients, was responsive to ethanol. These findings indicate that reduced inhibition to Purkinje cells is sufficient to induce a tremor phenotype, highlighting the importance of the cerebellum, inhibition, and Purkinje cells in tremor. Animals with a global knockout of the GABA subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABA from Purkinje cells is sufficient to produce a tremor phenotype, although this tremor is less severe than seen in animals with a global knockout. These findings illustrate that the cerebellum can play a key role in the genesis of the observed tremor phenotype.
先前，在 GABA 亚基全局敲除的动物中已经观察到一种类似特发性震颤的表型。鉴于小脑在震颤中的假设作用，包括特发性震颤，我们使用转基因小鼠选择性地从小脑浦肯野细胞中敲除 GABA 亚基。我们研究了这种表型对抑制性突触后电流、存活率、大运动能力和震颤表达的影响。浦肯野细胞特异性敲除 GABA 亚基消除了浦肯野细胞中所有 GABA 介导的抑制，而对小脑分子层中间神经元的 GABA 介导的抑制则完好无损。选择性地从小脑浦肯野细胞中丢失 GABA 不会导致加速转棒测试中的缺陷，也不会导致存活率降低。然而，无论性别或背景品系如何，都出现了震颤表型。这种震颤类似于 GABA 亚基全局敲除动物中的震颤，并且与患者中的特发性震颤一样，对乙醇有反应。这些发现表明，对浦肯野细胞的抑制减少足以诱导震颤表型，突出了小脑、抑制和浦肯野细胞在震颤中的重要性。GABA 亚基全局敲除的动物表现出类似于特发性震颤的震颤表型。在这里，我们表明从小脑浦肯野细胞中选择性敲除 GABA 足以产生震颤表型，尽管这种震颤比 GABA 亚基全局敲除动物中观察到的震颤要轻。这些发现表明小脑在观察到的震颤表型的发生中可以发挥关键作用。
