Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy

Neurology Pediatrics Medicine
mTOR pathway epileptic seizures cellular senescence

This is a research report on focal cortical dysplasia (FCD) type II. The authors aim to investigate the cellular senescence phenomenon present in FCD II and whether targeting these senescent cells can alleviate seizures.

Background: FCD II is a common cortical malformation causing childhood epilepsy and developmental delay. It is caused by somatic mosaic mutations in the PI3K-AKT-mTOR pathway genes (such as AKT3, DEPDC5, mTOR, PIK3CA, etc.). These mutations lead to overactivation of the mTOR pathway in some neurons, forming abnormal dysmorphic neurons (DNs) and balloon cells (BCs) scattered within the normal cortical tissue. FCD II is typically drug-resistant, requiring surgical resection of the epileptogenic zone. Elucidating the molecular mechanisms of DNs and BCs and their association with epileptic activity is crucial for identifying new therapeutic targets.

Research process: 1. Extracellular electrical activity was recorded from resected cortical tissues of two FCD II patients using microelectrode arrays. Regions with interictal-like discharges (IILDs) and multi-unit activity (MUA) were found, and the density of DNs correlated positively with these active regions.

  1. In 22 FCD II and 13 control tissue samples, immunostaining for senescence markers (SA-β-gal, p53, p16, etc.) revealed that DNs and BCs exhibited a senescent phenotype, while normal neurons and control tissues did not.

  2. In depdc5 knockout mouse models, neurons also exhibited a senescent phenotype, accompanied by mTOR pathway activation and a senescence-associated secretory phenotype (SASP).

  3. In the mtorS2215F mosaic mutation mouse model, continuous treatment with the senolytic drugs dasatinib/quercetin (D/Q) for 9 days reduced DNs by approximately 70% and lowered seizure frequency, which remained at a lower level even one month after drug withdrawal.

  4. D/Q showed no significant adverse effects in wild-type mice, and D/Q did not exhibit anti-seizure activity in the pentylenetetrazole-induced epilepsy model, suggesting that its therapeutic effect is due to targeting senescent cells.

Significance summary: This study is the first to discover the senescent phenotype of DNs and BCs in FCD II and link it to epileptic activity. Using the senolytic drug D/Q can selectively eliminate these pathogenic senescent cells, thereby alleviating seizures, opening up a new precision therapy strategy for mTOR pathway-related developmental epileptic cortical dysplasias. Since FCD II is a mosaic disease, senolytic therapy may be an effective ultra-precision treatment approach. This study provides new insights into targeted therapies for mTOR pathway-related disorders.

This research combines various techniques such as cellular electrophysiology, molecular pathology, genetic mouse models, and drug interventions, making it theoretically significant and clinically promising.