Selective loss of the GABAAα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype

Abstract

Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABA_Aα1 subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABA_Aα1 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_Aα1 subunit abolished all GABA_A-mediated inhibition in Purkinje cells, while leaving GABA_A-mediated inhibition to cerebellar molecular layer interneurons intact. Selective loss of GABA_Aα1 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_Aα1 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.NEW & NOTEWORTHY Animals with a global knockout of the GABA_Aα1 subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABA_Aα1 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.

Keywords: GABA; alcohol; cerebellum; essential tremor; inhibition.