Selective loss of the GABA Aα1 subunit from Purkinje cells is sufficient to induce a tremor phenotype.

Previously, an essential tremor-like phenotype has been noted in animals with a global knockout of the GABA(A alpha 1) subunit. Given the hypothesized role of the cerebellum in tremor, including essential tremor, we used transgenic mice to selectively knock out the GABA(A alpha 1) subunit from cerebellar Purkinje cells. We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of hemor. Purkinje cell specific knockout of the GABA(A alpha 1) subunit abolished all GABA(A)-mediated inhibition in Purkinje cells, while leaving GABA(A)-mediated inhibition to cerebellar molecular layer intemeurons intact. Selective loss of GABA(A alpha 1) 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(A alpha 1 )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(A alpha 1) subunit show a tremor phenotype reminiscent of essential tremor. Here we show that selective knockout of GABA(A alpha 1) 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.