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
- 1Institute of Physiology, Second Faculty of Medicine, Charles University
Abstract
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 Mtorp.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 MTORp.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 mTORmut (16.7%) and non-mTORmut (13.1%) neurons, with minimal loss in unmatched non-FCD controls. In IHC, lesions contained Beta-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 IC50, 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.
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BibTeX
@misc{olson2026chronic,
title = {{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}},
author = {C. V. Olson and N. Shariati and N. Prochazkova and K. Cizek and M. Rehorova and J. Populova and J. T. Rozlivkova and S. Wang and B. Ricketts and B. Kucerova and J. Kudlacek and B. Straka and P. Jiruska and O. Novak},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.19.726138},
url = {https://www.biorxiv.org/content/10.64898/2026.05.19.726138v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - 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
AU - C. V. Olson
AU - N. Shariati
AU - N. Prochazkova
AU - K. Cizek
AU - M. Rehorova
AU - J. Populova
AU - J. T. Rozlivkova
AU - S. Wang
AU - B. Ricketts
AU - B. Kucerova
AU - J. Kudlacek
AU - B. Straka
AU - P. Jiruska
AU - O. Novak
PY - 2026
DA - 2026/05/19
PB - bioRxiv
DO - 10.64898/2026.05.19.726138
UR - https://www.biorxiv.org/content/10.64898/2026.05.19.726138v2
AB - 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 Mtorp.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 MTORp.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 mTORmut (16.7%) and non-mTORmut (13.1%) neurons, with minimal loss in unmatched non-FCD controls. In IHC, lesions contained Beta-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 IC50, 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.
ER -