LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy

Francesco Rusconi, Leda Paganini, Daniela Braida, Luisa Ponzoni, Emanuela Toffolo, Annalisa Maroli, Nicoletta Landsberger, Francesco Bedogni, Emilia Turco, Linda Pattini, Fiorella Altruda, Silvia De Biasi, Mariaelvina Sala, Elena Battaglioli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2729-2740
Number of pages12
JournalCerebral Cortex
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 1 2015

Keywords

  • alternative splicing
  • epigenetics
  • epilepsy
  • Rett syndrome
  • transcription

ASJC Scopus subject areas

  • Medicine(all)

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    Rusconi, F., Paganini, L., Braida, D., Ponzoni, L., Toffolo, E., Maroli, A., Landsberger, N., Bedogni, F., Turco, E., Pattini, L., Altruda, F., De Biasi, S., Sala, M., & Battaglioli, E. (2015). LSD1 Neurospecific Alternative Splicing Controls Neuronal Excitability in Mouse Models of Epilepsy. Cerebral Cortex, 25(9), 2729-2740. https://doi.org/10.1093/cercor/bhu070