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.

LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior

“…The generation of a mouse model lacking microexon E8a (neuroLSD1 KO mice) allowed us to characterize neuroLSD1 as an in vivo modulator of hippocampal excitability. We reported that shifts in the LSD1/neuroLSD1 ratio in response to activity contribute dynamically to the control of neuronal excitability by participating in the transcriptional mechanism of homeostatic adaptation (15). In this work we implicate LSD1 and neuroLSD1 in shaping emotional behavior as fine tuners of psychosocial stress-evoked transcription of IEGs.…”

Alternative Splicing in the Mammalian Nervous System: Recent Insights into Mechanisms and Functional Roles

“…Previously, downregulation of RBFOX expression and misregulation of the RBFOX splicing regulatory network-comprising mostly longer alternative exons-were also observed in ASD patients (Voineagu et al, 2011;Weyn-Vanhentenryck et al, 2014). In addition, a recent study demonstrated that nSR100-and Nova1-mediated control of the inclusion of a 12-nt microexon in LSD1 (also known as KDM1A), a histone H3K4 demethylase, contributes to neuronal excitability in mice (Rusconi et al, 2014). This regulation was proposed to be important for susceptibility to seizure and could represent a molecular event that underlies epilepsy.…”

Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development

“…Furthermore, this altered pattern of inclusion in ASD subjects affects genes enriched in known genetic associations with ASD and is also highly correlated with reduced expression of nSR100 . Additional studies have linked microexon misregulation to schizophrenia and epilepsy (Ovadia and Shifman 2011;Rusconi et al 2014). In the future, it will be of considerable interest to address whether partial alteration of nSR100 levels in developing mice may contribute to phenotypes associated with human neurological disorders.…”