Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice

Yuki Matsushita, Yasunari Sakai, Mitsunori Shimmura, Hiroshi Shigeto, Miki Nishio, Satoshi Akamine, Masafumi Sanefuji, Yoshito Ishizaki, Hiroyuki Torisu, Yusaku Nakabeppu, Akira Suzuki, Hidetoshi Takada, Toshiro Hara

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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.

Original languageEnglish
Article number22991
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Mar 10 2016

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Pro-Opiomelanocortin
Premature Mortality
Malformations of Cortical Development
Epilepsy
Neurons
Seizures
Partial Epilepsy
Dentate Gyrus
Sirolimus
Knockout Mice
Cerebral Cortex
Hypertrophy
Fluorescent Antibody Technique
Comorbidity
Electroencephalography
Hippocampus
Phenotype
Brain
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

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Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice. / Matsushita, Yuki; Sakai, Yasunari; Shimmura, Mitsunori; Shigeto, Hiroshi; Nishio, Miki; Akamine, Satoshi; Sanefuji, Masafumi; Ishizaki, Yoshito; Torisu, Hiroyuki; Nakabeppu, Yusaku; Suzuki, Akira; Takada, Hidetoshi; Hara, Toshiro.

In: Scientific reports, Vol. 6, 22991, 10.03.2016.

Research output: Contribution to journalArticle

Matsushita, Yuki ; Sakai, Yasunari ; Shimmura, Mitsunori ; Shigeto, Hiroshi ; Nishio, Miki ; Akamine, Satoshi ; Sanefuji, Masafumi ; Ishizaki, Yoshito ; Torisu, Hiroyuki ; Nakabeppu, Yusaku ; Suzuki, Akira ; Takada, Hidetoshi ; Hara, Toshiro. / Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice. In: Scientific reports. 2016 ; Vol. 6.
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