Résumé
Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.
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•Chronic stress (CS) transiently elevates Klf9 expression in the hippocampus of mice•Klf9 silencing in male and female mice prevents CS-induced spine alterations•Klf9 silencing in male and female mice prevents CS-induced maladaptive fear responses•Hippocampal KLF9 levels are increased in women with CS exposure and MDD
Besnard et al. show that chronic stress induces a transient elevation in hippocampal Klf9 expression in mice and that KLF9 expression is upregulated in hippocampus of women with MDD. Genetic silencing of Klf9 expression prevents chronic stress-induced enlargements of dendritic spines and maladaptive fear responses in male and female mice.