Journal
EPILEPSIA
Volume 52, Issue 11, Pages 2065-2075Publisher
WILEY
DOI: 10.1111/j.1528-1167.2011.03280.x
Keywords
Mammalian target of rapamycin complex 1; Pten; Cortical dysplasia; Tuberous sclerosis complex; Mossy fiber sprouting
Categories
Funding
- NIH [R01NS 39943, 49427, R01NS 042616]
- Epilepsy Foundation [T32NS 43124, F32NS 56664]
- Citizens United for Research in Epilepsy (CURE)
- NIH from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development [P30HD 024064]
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Purpose: Increased activity of mTOR Complex 1 (mTORC1) has been demonstrated in cortical dysplasia and tuberous sclerosis complex, as well as in animal models of epilepsy. Recent studies in such models revealed that inhibiting mTORC1 with rapamycin effectively suppressed seizure activity. However, seizures can recur after treatment cessation, and continuous rapamycin exposure can adversely affect animal growth and health. Here, we evaluated the efficacy of an intermittent rapamycin treatment protocol on epilepsy progression using neuron subset-specific-Pten (NS-Pten) conditional knockout mice. Methods: NS-Pten knockouts were treated with a single course of rapamycin during postnatal weeks 4 and 5, or intermittently over a period of 5 months. Epileptiform activity was monitored using video-electroencephalography (EEG) recordings, and mossy fiber sprouting was evaluated using Timm staining. Survival and body weight were assessed in parallel. Key Findings: NS-Pten knockouts treated with a single course of rapamycin had recurrence of epilepsy 4-7 weeks after treatment ended. In contrast, epileptiform activity remained suppressed, and survival increased if knockout mice received additional rapamycin during weeks 10-11 and 16-17. Aberrant mossy fiber sprouting, present by 4 weeks of age and progressing in parallel with epileptiform activity, was also blocked by rapamycin. Significance: These findings demonstrate that a single course of rapamycin treatment suppresses epileptiform activity and mossy fiber sprouting for several weeks before epilepsy recurs. However, additional intermittent treatments with rapamycin prevented this recurrence and enhanced survival without compromising growth. Therefore, these studies add to the growing body of evidence implicating an important role for mTORC1 signaling in epilepsy.
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