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Published on: February 10, 2020
mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia
Lena H Nguyen1, Amy L Brewster, Madeline E Clark
1Department of Neuroscience, Baylor College of Medicine, Houston, Texas, U.S.A; The Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, U.S.A; The Gordon and Mary Cain Pediatric Neurology Research Foundation Laboratories, Texas Children's Hospital, Houston, Texas, U.S.A.
Objective:
Hyperactivation of the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) pathway has been demonstrated in human cortical dysplasia (CD) as well as in animal models of epilepsy. Although inhibition of mTOR signaling early in epileptogenesis suppressed epileptiform activity in the neuron subset-specific Pten knockout (NS-Pten KO) mouse model of CD, the effects of mTOR inhibition after epilepsy is fully established were not previously examined in this model. Here, we investigated whether mTOR inhibition suppresses epileptiform activity and other neuropathological correlates in adult NS-Pten KO mice with severe and well-established epilepsy.
Methods:
The progression of epileptiform activity, mTOR pathway dysregulation, and associated neuropathology with age in NS-Pten KO mice were evaluated using video-electroencephalography (EEG) recordings, Western blotting, and immunohistochemistry. A cohort of NS-Pten KO mice was treated with the mTOR inhibitor rapamycin (10 mg/kg i.p., 5 days/week) starting at postnatal week 9 and video-EEG monitored for epileptiform activity. Western blotting and immunohistochemistry were performed to evaluate the effects of rapamycin on the associated pathology.
Results:
Epileptiform activity worsened with age in NS-Pten KO mice, with parallel increases in the extent of hippocampal mTOR complex 1 and 2 (mTORC1 and mTORC2, respectively) dysregulation and progressive astrogliosis and microgliosis. Rapamycin treatment suppressed epileptiform activity, improved baseline EEG activity, and increased survival in severely epileptic NS-Pten KO mice. At the molecular level, rapamycin treatment was associated with a reduction in both mTORC1 and mTORC2 signaling and decreased astrogliosis and microgliosis.
Significance:
These findings reveal a wide temporal window for successful therapeutic intervention with rapamycin in the NS-Pten KO mouse model, and they support mTOR inhibition as a candidate therapy for established, late-stage epilepsy associated with CD and genetic dysregulation of the mTOR pathway.
Insights
Inhibition of the mechanistic target of rapamycin (mTOR) pathway suppressed established epilepsy in a mouse model. This suggests mTOR inhibition is a viable therapy for late-stage epilepsy associated with cortical dysplasia.
Area of Science:
- Neuroscience
- Molecular Biology
- Epilepsy Research
Background:
- Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cortical dysplasia (CD) and epilepsy.
- Previous studies showed early mTOR inhibition suppressed epileptiform activity in a mouse model of CD.
- The effect of mTOR inhibition on established epilepsy in this model remained unexamined.
Purpose of the Study:
- To investigate if mTOR inhibition can suppress established epileptiform activity and neuropathology in adult neuron subset-specific Pten knockout (NS-Pten KO) mice.
- To determine the therapeutic window for mTOR inhibition in a severe epilepsy model.
Main Methods:
- Evaluated epileptiform activity, mTOR pathway, and neuropathology in NS-Pten KO mice using video-EEG, Western blotting, and immunohistochemistry.
- Treated adult NS-Pten KO mice with the mTOR inhibitor rapamycin starting at postnatal week 9.
- Monitored EEG for epileptiform activity and assessed molecular and cellular changes post-treatment.
Main Results:
- Epileptiform activity worsened with age in NS-Pten KO mice, alongside increased mTORC1/2 dysregulation, astrogliosis, and microgliosis.
- Rapamycin treatment suppressed epileptiform activity and improved EEG in severely epileptic mice.
- Rapamycin reduced mTORC1/2 signaling, astrogliosis, and microgliosis, and increased survival.
Conclusions:
- mTOR inhibition demonstrates a wide therapeutic window for established epilepsy in the NS-Pten KO mouse model.
- These findings support mTOR inhibition as a potential therapy for late-stage epilepsy linked to CD and mTOR pathway genetic dysregulation.
