GNAO1 Mutant Mice and Movement Disorders

Abstract

Mutations in the gene GNAO1 have been associated with ultra-rare (ca. 200 patients) neurologic abnormalities including movement disorders, epilepsy, and developmental delay. Patients with these mutations often display symptoms at birth or in early childhood. GNAO1 codes for the alpha subunit (Gαo) of the G-protein Go, which is the most abundant membrane protein in the central nervous system.

Our lab developed a Gnao1+/- mouse line to mimic symptoms seen in patients with loss of function (LOF) mutations in GNAO1. We observed that these mutant mice had reduced inhibitory signaling in the cerebellum, which is important for movement coordination. My project will determine if there are structural changes in cerebellar neuron architecture to account for the altered inhibitory signaling, providing insights into the mechanism of LOF GNAO1 disorders and potential therapeutic opportunities. I will characterize the number of inhibitory neurons in the cerebellar molecular layer and the structure of their synapses on Purkinje cells. Preliminary studies suggest that although there are similar numbers of inhibitory interneurons in mutants, there are reductions in the size of inhibitory synapses from molecular layer neurons onto Purkinje cells. Future studies will confirm and extend these results to include other markers of cerebellar development. In my presentation, I will provide an introduction to the GNAO1 gene and its expression product Gαo, describe what we have observed in our mouse models, and present my project, including both pilot study results and ongoing research.