Comparison of gamma-aminobutyrate receptors in the medial vestibular nucleus of control and Scn8a mutant mice.

The Purkinje cells of the cerebellum provide inhibitory input to vestibular nucleus neurons, with gamma-aminobutyrate (GABA) as neurotransmitter. Using extracellular recordings and bath application of agonists and antagonists, we compared GABA receptors in the medial vestibular nucleus of brain slices from Scn8a mutant mice of med(J) type, in which there is greatly reduced spontaneous and evoked activity of Purkinje cells, to those in slices from control mice. Muscimol, an agonist at GABA(A) receptors, produced a larger reduction of firing rate in neurons of mutant mice than in neurons of control mice, whereas there was no difference for baclofen, an agonist at GABA(B) receptors. In most cases tested, the effects of muscimol and baclofen remained similar when synaptic transmission was blocked, suggesting that the effects were predominantly directly upon GABA receptors of the neurons being recorded from. The up-regulation of GABA(A) receptors was similar in magnitude to that previously found for rats with bilateral transection of the inferior cerebellar peduncle. It may relate in both cases to reduced Purkinje cell input to medial vestibular nucleus neurons. The lack of effect on GABA(B) receptors suggests that the changes found with peduncle transection may have resulted from something more than reduced Purkinje cell activity, such as reduced concentrations of GABA, or that reduction of Purkinje cell activity in Scn8a mutant mice was insufficient to affect GABA(B) receptors. Other possible explanations of the results cannot be excluded since the Scn8a mutation affects other neuron types besides Purkinje cells.