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mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia
Author(s) -
Nguyen Lena H.,
Brewster Amy L.,
Clark Madeline E.,
RegnierGolanov Angelique,
Sunnen C. Nicole,
Patil Vinit V.,
D'Arcangelo Gabriella,
Anderson Anne E.
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12946
Subject(s) - epileptogenesis , astrogliosis , epilepsy , mtorc1 , cortical dysplasia , pi3k/akt/mtor pathway , neuroscience , medicine , endocrinology , biology , signal transduction , central nervous system , microbiology and biotechnology
Summary Objective Hyperactivation of the mechanistic target of rapamycin (m TOR ; 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 m TOR signaling early in epileptogenesis suppressed epileptiform activity in the neuron subset‐specific Pten knockout ( NS ‐ P ten KO ) mouse model of CD , the effects of m TOR inhibition after epilepsy is fully established were not previously examined in this model. Here, we investigated whether m TOR inhibition suppresses epileptiform activity and other neuropathological correlates in adult NS ‐ P ten KO mice with severe and well‐established epilepsy. Methods The progression of epileptiform activity, m TOR pathway dysregulation, and associated neuropathology with age in NS ‐ P ten KO mice were evaluated using video–electroencephalography ( EEG ) recordings, Western blotting, and immunohistochemistry. A cohort of NS ‐ P ten KO mice was treated with the m TOR 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 ‐ P ten 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 ‐ P ten KO mice. At the molecular level, rapamycin treatment was associated with a reduction in both m TORC 1 and m TORC 2 signaling and decreased astrogliosis and microgliosis. Significance These findings reveal a wide temporal window for successful therapeutic intervention with rapamycin in the NS ‐ P ten KO mouse model, and they support m TOR inhibition as a candidate therapy for established, late‐stage epilepsy associated with CD and genetic dysregulation of the m TOR pathway.