Mice with monoallelic loss exhibit reduced inhibitory synaptic input to cerebellar Purkinje cells.

encodes Gα, a heterotrimeric G protein α subunit in the G family. In this report, we used a mouse model "G203R" previously described as a "gain-of-function" mutant with movement abnormalities and enhanced seizure susceptibility. Here, we report an unexpected second mutation resulting in a loss-of-function Gα protein, and describe alterations in central synaptic transmission. Whole cell patch clamp recordings from Purkinje cells (PCs) in acute cerebellar slices from mutant mice showed significantly lower frequencies of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) compared with WT mice. There was no significant change in sEPSCs or mEPSCs. Whereas mIPSC frequency was reduced, mIPSC amplitudes were not affected, suggesting a presynaptic mechanism of action. A modest decrease in the number of molecular layer interneurons was insufficient to explain the magnitude of IPSC suppression. Paradoxically, G inhibitors (pertussis toxin) enhanced the mutant-suppressed mIPSC frequency and eliminated the difference between WT and mice. Although GABA receptor regulates mIPSCs, neither agonists nor antagonists of this receptor altered function in the mutant mouse PCs. This study is an electrophysiological investigation of the role of G protein in cerebellar synaptic transmission using an animal model with a loss-of-function G protein. This report reveals the electrophysiological mechanisms of a movement disorder animal model with monoallelic loss. This study illustrates the role of Gα protein in regulating GABA release in mouse cerebellum. This study could also facilitate the discovery of new drugs or drug repurposing for -associated disorders. Moreover, since shares pathways with other genes related to movement disorders, developing drugs for the treatment of -associated movement disorders could further the pharmacological intervention for other monogenic movement disorders.