title: Rapamycin reverses status epilepticus-induced memory deficits and dendritic damage.
abstract: Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.
authors.affiliation: Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Brewster
authors.forename: Joaquin N
authors.initials: JN
authors.lastname: Lugo
authors.forename: Vinit V
authors.initials: VV
authors.lastname: Patil
authors.forename: Wai L
authors.initials: WL
authors.lastname: Lee
authors.forename: Yan
authors.initials: Y
authors.lastname: Qian
authors.forename: Fabiola
authors.initials: F
authors.lastname: Vanegas
authors.forename: Anne E
authors.initials: AE
authors.lastname: Anderson
mesh_terms: D000818:Animals; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D005911:Gliosis; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010862:Pilocarpine / Q000009:adverse effects; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007473:Ion Channels; D046912:Multiprotein Complexes; D010862:Pilocarpine; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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