SRF and SRFΔ5 Splicing Isoform Recruit Corepressor LSD1/KDM1A Modifying Structural Neuroplasticity and Environmental Stress Response

Abstract

Ten to 20% of western countries population suffers from major depression disorder (MDD). Stressful life events represent the main environmental risk factor contributing to the onset of MDD and other stress-related neuropsychiatric disorders. In this regard, investigating brain physiology of stress response underlying the remarkable individual variability in terms of behavioral outcome may uncover stress-vulnerability pathways as a source of candidate targets for conceptually new antidepressant treatments. Serum response factor (SRF) has been addressed as a stress transducer via promoting inherent experience-induced Immediate Early Genes (IEGs) expression in neurons. However, in resting conditions, SRF also represents a transcriptional repressor able to assemble the core LSD1/CoREST/HDAC2 corepressor complex, including demethylase and deacetylase activities. We here show that dominant negative SRF splicing isoform lacking most part of the transactivation domain, namely SRFΔ5, owes its transcriptional repressive behavior to the ability of assembling LSD1/CoREST/HDAC2 corepressor complex meanwhile losing its affinity for transcription-permissive cofactor ELK1. SRFΔ5 is highly expressed in the brain and developmentally regulated. In the light of its activity as negative modulator of dendritic spine density, SRFΔ5 increase along with brain maturation suggests a role in synaptic pruning. Upon acute psychosocial stress, SRFΔ5 isoform transiently increases its levels. Remarkably, when stress is chronically repeated, a different picture occurs where SRF protein becomes stably upregulated in vulnerable mice but not in resilient animals. These data suggest a role for SRFΔ5 that is restricted to acute stress response, while positive modulation of SRF during chronic stress matches the criteria for stress-vulnerability hallmark.

Keywords: Alternative splicing; Hippocampal neurons; Lysine specific demethylase 1; Neuronal structural plasticity; Psychosocial stress; Serum response factor; Stress vulnerability.