Loss of Inhibitory Neuron AMPA Receptors Contributes to Ataxia and Epilepsy inStargazerMice

Abstract

Stargazermice are characterized by ataxia and seizures, which resemble the human disorder absence epilepsy. Stargazin, the protein mutated instargazermice, promotes the expression and function of neuronal AMPA receptors (AMPARs). However, it is unclear how decreased expression of excitatory AMPARs generatesstargazerseizures, given that seizures often result from increased neuronal excitability. Additionally, althoughstargazerataxia has been attributed to loss of AMPARs from cerebellar granule cells, other cerebellar neurons have not been examined. To examine the role of AMPAR dysfunction in these behavioral phenotypes, electrophysiological recordings were used to probe AMPAR regulation in relevant brain regions. We found that both cerebellar Purkinje cells and inhibitory thalamic reticular nucleus neurons have strongly reduced synaptic AMPAR function instargazermice. Together, our data suggest that impaired AMPAR regulation in multiple neuron populations may contribute to the behavioral phenotypes of absence seizures and ataxia seen instargazermice and imply that an understanding of human genetic disorders will require knowledge of both the genes that are mutated as well as their precise cellular expression pattern.