title: Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio-temporal lobe epilepsy.
abstract: Recent studies in animal models have suggested that the mammalian target of rapamycin (mTOR) signaling pathway is involved in several features of mesio-temporal lobe epilepsy (MTLE), and that its inhibition could have therapeutic interests. However, it remains controversial whether mTOR activation is the cause or the consequence of MTLE. We previously showed in a mouse model of MTLE associated with hippocampal sclerosis that increased neuronal excitability and brain-derived neurotrophic factor (BDNF) overexpression contribute to the development of morphological features of this form of epilepsy. Here, we addressed whether mTOR activation promotes MTLE epileptogenesis via increasing neuronal excitability and/or BDNF expression or rather mediates neuroplasticity associated with hippocampal sclerosis. In mice injected intrahippocampally with kainate (1 nmol), we showed a biphasic increase of phospho-S6 (p-S6) ribosomal protein expression, the downstream product of the mTOR signaling pathway, in the dispersed granule cell layer (GCL) of the dentate gyrus with a second phase lasting up to 6 months. Chronic treatment with rapamycin suppressed p-S6 expression, granule cell dispersion and mossy fiber sprouting, but did not reduce cell loss, BDNF overexpression, glutamic acid decarboxylase (GAD)67 expression or the development of hippocampal paroxysmal discharges. Neuronal inhibition by midazolam (2 × 10 mg/kg, i.p.) abolished the increased expression of p-S6 in the dispersed GCL. Our data suggest that activation of the mTOR signaling pathway results from the increased neuronal excitation that develops in the GCL and may contribute to MTLE morphological changes. However, these data do not support the role of this pathway in the development of MTLE or its inhibition as a therapy for this form of epilepsy.
authors.affiliation: Department of Neurosurgery, Shiga University of Medical Science, Seta-Tsukinowa-Cho, Otsu, Shiga, 520-2192, Japan; Department of Neurosurgery, Koto Memorial Hospital, Higashioumi, Shiga, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shima
authors.forename: Naoki
authors.initials: N
authors.lastname: Nitta
authors.forename: Fumio
authors.initials: F
authors.lastname: Suzuki
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Laharie
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nozaki
authors.forename: Antoine
authors.initials: A
authors.lastname: Depaulis
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002491:Central Nervous System Agents; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid; D008297:Male; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002491:Central Nervous System Agents; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D008874:Midazolam; D007608:Kainic Acid; D020123:Sirolimus
keywords: BDNF; GABA; epileptogenesis; granule cell dispersion; mossy fiber sprouting