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.