title: LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy.
abstract: Alternative splicing in the brain is dynamic and instrumental to adaptive changes in response to stimuli. Lysine-specific demethylase 1 (LSD1/KDM1A) is a ubiquitously expressed histone H3Lys4 demethylase that acts as a transcriptional co-repressor in complex with its molecular partners CoREST and HDAC1/2. In mammalian brain, alternative splicing of LSD1 mini-exon E8a gives rise to neuroLSD1, a neurospecific isoform that, upon phosphorylation, acts as a dominant-negative causing disassembly of the co-repressor complex and de-repression of target genes. Here we show that the LSD1/neuroLSD1 ratio changes in response to neuronal activation and such effect is mediated by neurospecific splicing factors NOVA1 and nSR100/SRRM4 together with a novel cis-silencer. Indeed, we found that, in response to epileptogenic stimuli, downregulation of NOVA1 reduces exon E8a splicing and expression of neuroLSD1. Using behavioral and EEG analyses we observed that neuroLSD1-specific null mice are hypoexcitable and display decreased seizure susceptibility. Conversely, in a mouse model of Rett syndrome characterized by hyperexcitability, we measured higher levels of NOVA1 protein and upregulation of neuroLSD1. In conclusion, we propose that, in the brain, correct ratio between LSD1 and neuroLSD1 contributes to excitability and, when altered, could represent a pathogenic event associated with neurological disorders involving altered E/I.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rusconi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Leda
authors.initials: L
authors.lastname: Paganini
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braida
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponzoni
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Toffolo
authors.affiliation: Department of Medical Biotechnology and Translational Medicine.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Maroli
authors.affiliation: Theoretical and Applied Sciences, Division of Biomedical Research, University of Insubria, Busto Arsizio 21052, Italy San Raffaele Rett Research Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Landsberger
authors.affiliation: San Raffaele Rett Research Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bedogni
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università Degli Studi di Torino, Turin 10126, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.affiliation: Dipartimento di Elettronica, Informazione e Bioingegneria-Politecnico di Milano, Milan, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Pattini
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, Università Degli Studi di Torino, Turin 10126, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.affiliation: Department of Biosciences, Università Degli Studi di Milano, Milan 20122, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: De Biasi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine CNR, Institute of Neuroscience, Milan, Italy.
authors.forename: Mariaelvina
authors.initials: M
authors.lastname: Sala
authors.affiliation: Department of Medical Biotechnology and Translational Medicine CNR, Institute of Neuroscience, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Battaglioli
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics*; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000090682:Neuro-Oncological Ventral Antigen; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins; D056466:Histone Demethylases; C504076:KDM1a protein, mouse
keywords: Rett syndrome; alternative splicing; epigenetics; epilepsy; transcription