Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy.
Dentate granule cell axon (mossy fiber) sprouting is a common abnormality in patients with temporal lobe epilepsy. Mossy fiber sprouting creates an aberrant positive-feedback network among granule cells that does not normally exist. Its role in epileptogenesis is unclear and controversial. If it were possible to block mossy fiber sprouting from developing after epileptogenic treatments, its potential role in the pathogenesis of epilepsy could be tested. Previous attempts to block mossy fiber sprouting have been unsuccessful. The present study targeted the mammalian target of rapamycin (mTOR) signaling pathway, which regulates cell growth and is blocked by rapamycin. Rapamycin was focally, continuously, and unilaterally infused into the dorsal hippocampus for prolonged periods beginning within hours after rats sustained pilocarpine-induced status epilepticus. Infusion for 1 month reduced aberrant Timm staining (a marker of mossy fibers) in the granule cell layer and molecular layer. Infusion for 2 months inhibited mossy fiber sprouting more. However, after rapamycin infusion ceased, aberrant Timm staining developed and approached untreated levels. When onset of infusion began after mossy fiber sprouting had developed for 2 months, rapamycin did not reverse aberrant Timm staining. These findings suggest that inhibition of the mTOR signaling pathway suppressed development of mossy fiber sprouting. However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization.
Buckmaster
Paul S
PS
Department of Comparative Medicine, Stanford University, Stanford, California 94305, USA. psb@stanford.edu
Ingram
Elizabeth A
EA
Wen
Xiling
X
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001286:Atropine Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010276:Parasympatholytics / Q000008:administration & dosage / Q000494:pharmacology; D010862:Pilocarpine / Q000008:administration & dosage / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D013194:Staining and Labeling; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D000927:Anticonvulsants; D001286:Atropine Derivatives; D018721:Muscarinic Agonists; D010276:Parasympatholytics; D010862:Pilocarpine; C006649:methylatropine; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus