title: Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain.
abstract: Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential, as it has been shown to reduce seizure frequency and seizure severity in rodent models. Here, we tested whether mTOR signaling facilitates abnormal development of granule cells during epileptogenesis. We also examined dentate inflammation and mossy cell death in the dentate hilus. To determine if mTOR activation is necessary for abnormal granule cell development, transgenic mice that harbored fluorescently-labeled adult-born granule cells were treated with rapamycin following pilocarpine-induced status epilepticus. Systemic rapamycin effectively blocked phosphorylation of S6 protein (a readout of mTOR activity) and reduced granule cell mossy fiber axon sprouting. However, the accumulation of ectopic granule cells and granule cells with aberrant basal dendrites was not significantly reduced. Mossy cell death and reactive astrocytosis were also unaffected. These data suggest that anti-epileptogenic effects of mTOR inhibition may be mediated by mechanisms other than inhibition of these common dentate pathologies. Consistent with this conclusion, rapamycin prevented pathological weight gain in epileptic mice, suggesting that rapamycin might act on central circuits or even peripheral tissues controlling weight gain in epilepsy.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hester
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45267, United States.
authors.forename: Bethany E
authors.initials: BE
authors.lastname: Hosford
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Physiology, Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil.
authors.forename: Victor R
authors.initials: VR
authors.lastname: Santos
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors.forename: Shatrunjai P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45267, United States.
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Rolle
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors.forename: Candi L
authors.initials: CL
authors.lastname: LaSarge
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Liska
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil.
authors.forename: Norberto
authors.initials: N
authors.lastname: Garcia-Cairasco
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Departments of Anesthesia and Pediatrics, University of Cincinnati, Cincinnati, OH 45267, United States; Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45267, United States. Electronic address: steve.danzer@cchmc.org.
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D027682:Cation Transport Proteins; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000473:pathology; D010862:Pilocarpine / Q000633:toxicity; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000627:therapeutic use*; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000628:therapy*; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; C498520:Gli1 protein, mouse; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D000071676:Zinc Finger Protein GLI1; D010862:Pilocarpine; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus
keywords: Dentate granule cell; Dentate gyrus; Epilepsy; Epileptogenesis; Hippocampus; Inflammation; Mossy fiber sprouting; Neurogenesis; Obesity; Rapamycin; mTOR