title: Kainic Acid Induces mTORC1-Dependent Expression of Elmo1 in Hippocampal Neurons.
abstract: Epileptogenesis is a process triggered by initial environmental or genetic factors that result in epilepsy and may continue during disease progression. Important parts of this process include changes in transcriptome and the pathological rewiring of neuronal circuits that involves changes in neuronal morphology. Mammalian/mechanistic target of rapamycin (mTOR) is upregulated by proconvulsive drugs, e.g., kainic acid, and is needed for progression of epileptogenesis, but molecular aspects of its contribution are not fully understood. Since mTOR can modulate transcription, we tested if rapamycin, an mTOR complex 1 inhibitor, affects kainic acid-evoked transcriptome changes. Using microarray technology, we showed that rapamycin inhibits the kainic acid-induced expression of multiple functionally heterogeneous genes. We further focused on engulfment and cell motility 1 (Elmo1), which is a modulator of actin dynamics and therefore could contribute to pathological rewiring of neuronal circuits during epileptogenesis. We showed that prolonged overexpression of Elmo1 in cultured hippocampal neurons increased axonal growth, decreased dendritic spine density, and affected their shape. In conclusion, data presented herein show that increased mTORC1 activity in response to kainic acid has no global effect on gene expression. Instead, our findings suggest that mTORC1 inhibition may affect development of epilepsy, by modulating expression of specific subset of genes, including Elmo1, and point to a potential role for Elmo1 in morphological changes that accompany epileptogenesis.
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland. mblazejczyk@iimcb.gov.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Blazejczyk
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Matylda
authors.initials: M
authors.lastname: Macias
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St, 31-343, Krakow, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Korostynski
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Marcelina
authors.initials: M
authors.lastname: Firkowska
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St, 31-343, Krakow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Piechota
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Skalecka
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tempes
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Koscielny
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Urbanska
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna St, 31-343, Krakow, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Przewlocki
authors.affiliation: International Institute of Molecular and Cell Biology, 4 Ks. Trojdena St., 02-109, Warsaw, Poland. jaworski@iimcb.gov.pl.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jaworski
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016000:Cluster Analysis; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; C515800:ELMO1 protein, rat; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007608:Kainic Acid; D020123:Sirolimus
keywords: Elmo1; Epilepsy; Gene expression; Rapamycin; mTORC1