The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy.
Understanding molecular mechanisms mediating epileptogenesis is critical for developing more effective therapies for epilepsy. We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis, and mTOR inhibitors prevent epilepsy in a mouse model of tuberous sclerosis complex. Here, we investigated the potential role of mTOR in a rat model of temporal lobe epilepsy initiated by status epilepticus. Acute kainate-induced seizures resulted in biphasic activation of the mTOR pathway, as evident by an increase in phospho-S6 (P-S6) expression. An initial rise in P-S6 expression started approximately 1 h after seizure onset, peaked at 3-6 h, and returned to baseline by 24 h in both hippocampus and neocortex, reflecting widespread stimulation of mTOR signaling by acute seizure activity. After resolution of status epilepticus, a second increase in P-S6 was observed in hippocampus only, which started at 3 d, peaked 5-10 d, and persisted for several weeks after kainate injection, correlating with the development of chronic epileptogenesis within hippocampus. The mTOR inhibitor rapamycin, administered before kainate, blocked both the acute and chronic phases of seizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous epilepsy. Late rapamycin treatment, after termination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fiber sprouting and epilepsy but not neurogenesis or neuronal death. These findings indicate that mTOR signaling mediates mechanisms of epileptogenesis in the kainate rat model and that mTOR inhibitors have potential antiepileptogenic effects in this model.
Zeng
Ling-Hui
LH
Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Rensing
Nicholas R
NR
Wong
Michael
M
D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005452:Fluoresceins; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D007608:Kainic Acid; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology; D009930:Organic Chemicals / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014741:Video Recording / Q000379:methods
D005452:Fluoresceins; D007166:Immunosuppressive Agents; D009930:Organic Chemicals; C435731:fluoro jade; D011494:Protein Kinases; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D001973:Bromodeoxyuridine; D007608:Kainic Acid; D020123:Sirolimus