title: Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice.
abstract: Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6-8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsushita
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Shimmura
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shigeto
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akamine
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sanefuji
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ishizaki
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Torisu
authors.affiliation: Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
mesh_terms: D000818:Animals; D019465:Craniofacial Abnormalities; D018891:Dentate Gyrus / Q000254:growth & development / Q000473:pathology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D006801:Humans; D054220:Malformations of Cortical Development / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D011333:Pro-Opiomelanocortin; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus