A novel role for LSD1 splicing modulation in homeostatic adaptation to chronic stress

The stress response serves as a protective mechanism to address daily challenges, yet it's crucial for it to cease when the threat subsides, as prolonged stress engagement links to higher vulnerability to neuropsychiatric disorders.Lysine Specific Demethylase 1 (LSD1) is an epigenetic enzyme participating in the CoREST/HDAC2 corepressor complex regulating neuronal plasticity-related gene transcription. In the mammalian brain, LSD1 activity is modulated by its neurospecific splicing isoform neuroLSD1, lacking co-repressive activity as long as the ability to recruit corepressor partners. Numerous studies have compellingly demonstrated that when faced with potent environmental stimuli, LSD1/neuroLSD1 ratio is prompted toward LSD1 by splicing regulation, promoting an overall reduction of the stress-induced plasticity-related mechanisms of hippocampal glutamatergic neurons.In this project, we established an animal model of chronic psychosocial stress based on a modified version of the Chronic Social Defeat Stress paradigm, which allowed us to cluster behaviorally resilient and susceptible animals. The behavioral-guided clustering of susceptible animals correlates to decreased LSD1 hippocampal levels, unraveling a mechanism of desensitization of the splicing modulation mechanism after sustained stress in a subset of susceptible animals. In parallel, molecular-guided clustering, based on LSD1 levels, shows that animals with higher LSD1 expression rank within resilient behavioral profile.Relevantly, data obtained from post-mortem human hippocampal of suicide samples feature decreased levels of LSD1.These data preliminarily support a role for LSD1 in the biology of environmental stress resiliency, a hot topic of neuropsychopharmacology.