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

Abstract

Background and Purpose GRIN ‐related disorders are neurodevelopmental disorders caused by mutations in N‐methyl‐D‐aspartate receptor ( NMDAR ) subunit genes. A large fraction of these mutations lead to a ‘gain of function’ (GoF) of the NMDAR . 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 GluN2A . The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B ‐containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A (N615S) homozygous mutation ( Grin2a S/S mice). Experimental Approach Grin2a S/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 Results Radiprodil significantly and dose‐dependently reduced the onset and severity of AGS in Grin2a S/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 Implications Overall, 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.

Topics & Concepts