Radiprodil, a selective GluN2B negative allosteric modulator, rescues audiogenic seizures in mice carrying the GluN2A(N615S) mutation

Background and PurposeGRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor () subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the . Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of . The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of -containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the (N615S) homozygous mutation (Grin2aS/S mice).Experimental ApproachGrin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction.Key ResultsRadiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice.Conclusion and ImplicationsOverall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.