MTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia. (6th March 2015)

• Record Type: Journal Article
• Authors: Nguyen, Lena H.; Brewster, Amy L.; Clark, Madeline E.; Regnier‐Golanov, Angelique; Sunnen, C. Nicole; Patil, Vinit V.; D'Arcangelo, Gabriella; Anderson, Anne E.
• Is Part Of: Epilepsia. Volume 56:issue 4(2015:Apr.)
• Page Start: 636
• Page End: 646
• Publication Date: 2015-03-06
• Subjects: Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.12946
• Languages: English
• ISSNs: 0013-9580

Abstract

<abstract abstract-type="main" id="epi12946-abs-0001"> <title>Summary</title> <sec id="epi12946-sec-0001" sec-type="section"> <title>Objective</title> <p>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 <italic>Pten</italic> knockout (<italic>NS‐Pten </italic>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‐<italic>Pten </italic>KO mice with severe and well‐established epilepsy.</p> </sec> <sec id="epi12946-sec-0002" sec-type="section"> <title>Methods</title> <p>The progression of epileptiform activity, mTOR pathway dysregulation, and associated neuropathology with age in NS‐<italic>Pten </italic>KO mice were evaluated using video–electroencephalography (EEG) recordings, Western blotting, and immunohistochemistry. A cohort of NS‐<italic>Pten </italic>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.</p> </sec> <sec id="epi12946-sec-0003" sec-type="section"> <title>Results</title> <p>Epileptiform activity worsened with age in NS‐<italic>Pten </italic>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‐<italic>Pten </italic>KO mice. At the molecular level, rapamycin treatment was associated with a reduction in both mTORC1 and mTORC2 signaling and decreased astrogliosis and microgliosis.</p> </sec> <sec id="epi12946-sec-0004" sec-type="section"> <title>Significance</title> <p>These findings reveal a wide temporal window for successful therapeutic intervention with rapamycin in the NS‐<italic>Pten </italic>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.</p> </sec> </abstract>