Inhibition of Hdac3 during immune stimulus ameliorates sex-specific depressive-like behaviour and aberrant microglial morphology in the amygdala

Major depressive disorder (MDD) or ‘depression’ is a common illness worldwide that affects 3.8% of the population. Globally, women are diagnosed with depression twice as often as men; an effect with both biological and socioeconomic underpinnings. Rodent models have elucidated various sex differences in the neurobiology of depression in the brain. Although brain inflammation is a hallmark symptom of depression in both human and rodent studies, none of the currently prescribed antidepressants target inflammation. In the brain, microglia are primary regulators of inflammation as they activate inflammatory machinery in response to environmental changes. Acutely, microglial responses are beneficial but chronic microglial- driven inflammation can lead to brain and behavioural impairment. Thus, untapped therapeutic potential lies in understanding the mechanistic switch between acute, beneficial responses and chronic, aberrant responses of microglia. One way that microglial activity is controlled is through epigenetic regulation of gene expression. Histone deacetylases (Hdacs) are one class of enzymes that control gene expression by removing acetyl groups from lysine residues on histone tails, facilitating DNA-histone contacts. Hdac3 is the most widely expressed Hdac in the brain, and pharmacological inhibition of Hdac3’s deacetylase activity has neuroprotective and functional recovery benefits in models of ischemic stroke and spinal cord injury. The current study aimed to investigate the sex-specific neuroprotective effects of Hdac3 inhibition during 5 days of lipopolysaccharide (LPS) immune challenge; a common mouse model of depression. Hdac3 inhibition during the LPS immune challenges ameliorated LPS-induced depressive like behaviour on the sucrose preference test in females and tail suspension test in males. Microglial morphology analysis demonstrated increased branching and junctions in the lateral and basolateral amygdala of female LPS-treated mice compared to PBS controls. This phenotype was rescued with RGFP966 treatment. Overall, this research demonstrates the neuroprotective effects of Hdac3 inhibition during a microglial-mediated neuroimmune response and presents Hdac3 as a potential epigenetic therapeutic target to control microglial function in MDD.Medicine, Faculty ofGraduat