Abstracts

Rationale: The stargazer mouse has a mutation in Cacng2, the gene encoding stargazin, a TARP protein that traffics AMPA receptors to the postsynaptic membrane in cerebellar granule cells. It is currently not known whether AMPA receptors membrane expression is altered in forebrain neurons, and if so, how a deficit in glutamate signaling leads to absence seizures. We hypothesized that if fast spiking cortical interneurons in stargazer mice show decreased AMPA receptor trafficking, then impaired glutamatergic transmission onto cortical inhibitory interneurons may disinhibit the thalamocortical circuit, favoring spike-wave seizure generation.Methods: We compared the soma to dendrite expression ratio of the AMPA receptor subunit GluR4 in cortical parvalbumin+ interneurons in adult stargazer versus wild-type littermate mice using densitometry of specific antiGluR4 fluorescent antibody staining in coronal brain sections. We administered GYKI 52466, an AMPA receptor antagonist, intraperitoneally during videoEEG monitoring in mutant and wild type mice to determine the effects of selective reduction in excitatory transmission on absence seizures. Results: Parvalbumin+ cortical interneurons showed a near two-fold increase in the GluR4 soma:dendrite ratio in stargazer mice compared to wild-type controls (196%, p<0.0001, n= 18 stg, 15 +/+, Figure 1), consistent with impaired trafficking of dendritic AMPA receptors in the mutant. Confocal microscopy of transparent projections through the cell body of a representative parvalbumin+ cortical interneuron in a