Dasatinib-Quercetin May Reduce Senescence Markers, Without Senolysis or Seizure Modification, in a Mouse Model of Focal Cortical Dysplasia

Abstract

Mounting evidence from surgical type II focal cortical dysplasia (FCD) tissues and mouse models have recently shown that dysmorphic neurons carrying MTOR mutations (DNs) in FCD exhibit hallmarks of cellular senescence. Building on pioneering work from the Baulac group identifying cellular senescence as a feature of mTOR-pathway FCD, a recent study by Ribierre et al. (2024) [1] proposed oral dasatinib and quercetin (DQ) as a therapy that partially decreases the load of mutant, senescent neurons and thus reduces seizure occurrence in FCD mice. Using a different mouse strain and a different gain-of-function mutation in MTOR, our data confirm the presence of senescence hallmarks in FCD mice, but do not support one of the conclusions of Ribierre et al.--that DQ acts as a senolytic in an FCD mouse model--and we propose an alternative interpretation. We longitudinally tracked individual cell fate using two-photon microscopy and complemented these data with EEG monitoring and immunohistochemistry. Immunohistochemical analyses were performed within the same sections using multiple markers, allowing direct identification of mutant neurons and assessment of senescence-associated labeling. While we observed a detectable reduction in a senescence-associated marker, consistent with a senomorphic effect, it did not translate into a change in seizure phenotype, despite treatment timing and dosing matching those in the original study. For detailed materials and methods, see Extended Methods.