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

Abstract

BackgroundIncreased circuit level insights into Essential tremor, the most prevalent movement disorder, are needed. Previously, an Essential Tremor-like phenotype was noted in animals with a global knockout of the GABAA1 subunit. However, global knockout of the GABAA1 subunit has limitations, including potential early mortality and limited circuit level insights into the tremor.\n\nMethodsGiven the hypothesized role of the cerebellum in tremor, including Essential Tremor, we used transgenic mice to selectively knock out the GABAA1 subunit from cerebellar Purkinje cells. As previous work suggested background strain may influence phenotype in this model, we used two different background strains (a Black6 and a Mixed background). We examined the resulting phenotype regarding impacts on inhibitory postsynaptic currents, survival rates, gross motor abilities, and expression of tremor.\n\nResultsWe found that GABAA-mediated synaptic currents are abolished in Purkinje cells from Purkinje cell specific knockout mice, while GABAA-mediated inhibition to cerebellar molecular layer interneurons remains intact. Selective loss of GABAA1 from Purkinje cells did not produce gross motor deficits, as measured by 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 GABAA1 subunit, and, like Essential Tremor in patients, was responsive to ethanol.\n\nConclusionsThese 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.