Work

Chronic In Vivo Imaging of a Focal Cortical Dysplasia Mouse Model Reveals Progressive Neuronal Loss with No Senolytic or Antiseizure Efficacy Following Dasatinib–Quercetin Treatment

Year: 2026

Type: preprint

Abstract: Summary Objective Focal cortical dysplasia (FCD) type II is a common cause of pediatric drug-resistant epilepsy with no disease-modifying treatment. It arises from somatic mutations in the mTOR pathway that produce a mosaic population of mTOR-hyperactive dysmorphic neurons (DNs) with a senescence phenotype. A recent report showed that oral dasatinib– quercetin (DQ), both putative senolytics, selectively eliminates these neurons and abolishes seizures in an Mtor p.S2215F model. However, this has not been tested in a second FCD model and neuron loss was shown only by cross-sectional histology. Methods Using chronic cranial windows and longitudinal in vivo two-photon imaging, we tracked genetically labeled neurons over eight weeks. In a mosaic MTOR p.L2427P FCD model on a C57BL/6J background, we combined imaging with continuous video-EEG, immunohistochemistry (IHC), and LC–MS/MS pharmacokinetics in 47 mice. Seizure and pharmacokinetic sampling were extended to a smaller Swiss/CD1 cohort, the strain used previously. Results Imaging revealed progressive loss of mTOR mut (16.7%) and non-mTOR mut (13.1%) neurons, with minimal loss in unmatched non-FCD controls. In IHC, lesions contained β-galactosidase-positive (B-Gal + ) cells, but oral DQ showed no evidence of eliminating DNs or reducing seizure frequency, duration, or burden; seizures also persisted in CD1 mice. B-Gal + cells tended to be less dense after DQ, but not significantly after correction. These data are more consistent with a senomorphic than a senolytic effect. Brain dasatinib (median 8.5 nM) exceeded its Src/ABL IC 50 , whereas quercetin (median 12 nM) was nearly two orders of magnitude below its BCL-XL affinity. Significance Longitudinal tracking of single neurons shows progressive loss of labeled neurons in an FCD model, whereas the reported senolytic and antiseizure effects of DQ were not reproduced. DQ should not be assumed to act as a senolytic across FCD models, strains, or MTOR variants. Dependence on strain, mutation, or brain exposure bears on clinical translation. Key Points Longitudinal in vivo two-photon imaging showed progressive loss of mTOR-mutant neurons in an FCD type II mouse model Oral dasatinib–quercetin treatment did not eliminate dysmorphic neurons or reduce seizures in C57BL/6J mice; seizures persisted in CD1 mice Dasatinib–quercetin did not eliminate neurons or abolish seizures in an MTOR p.L2427P FCD model, so its efficacy may not generalize

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.05.19.726138