Ketamine produces antidepressant effects by inhibiting histone deacetylases and upregulating hippocampal BDNF levels in a DFP-based rat model of Gulf War Illness .

Approximately one-third of Gulf War veterans suffer from Gulf War Illness ( GWI), which encompass mood disorders and depressive symptoms. Deployment-related exposure to organophosphate (OP) compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased Brain Derived Neurotrophic Factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the FDA for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here we investigated whether KET's effect on histone mechanisms signal BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once-daily with diisopropyl fluorophosphate (DFP, 0.5 mg/kg s.c., 5-d). At 6-m following DFP exposure, KET (10 mg/kg, i.p.) was injected and brains were dissected 24-h later. Western blotting was utilized for protein expression and epigenetic studies utilized chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of HDAC enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involves the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathological synaptic plasticity and exerts an antidepressant effect in DFP rats. Significance Statement Our research offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated BDNF expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.