Genetic, molecular, and neurobiological determinants of post-traumatic stress disorder-related behaviour in mice

Abstract

Post-traumatic stress disorder (PTSD), a debilitating mental health condition, can occur as a consequence of exposure to a traumatic, potentially life-threatening event or series of events. Debilitating intrusive thoughts, hyperarousal, and negative alterations to cognition and mood are symptoms that persist over time, often becoming progressively worse. The modest efficacy of treatment options for PTSD highlights a crisis in PTSD drug development necessitating the discovery of novel pharmacological drug targets. One potential target is microglia, the brains immune cells, which are implicated in stress responses and dendritic spine remodelling and may explain grey matter reductions in PTSD. We report elevated densities of hyper-ramified microglial cells across stress-responsive corticolimbic structures coinciding with neuronal dendritic spine loss 32 days after footshock. We then investigated genetic vulnerability for PTSD through deletion of P-glycoprotein (P-gp), a transporter regulating brain uptake of corticosteroid stress hormones. P-gp knockout (KO) increased depression and anxiety-related behaviours, however, decreased conditioned fear responses following footshock. Independent of genotype, footshock decreased microglial density in several amygdaloid nuclei. Irrespective of footshock, P-gp KO led to an increased number of hypo-ramification microglia in the CA3. Finally, we investigated the effect of genetic deletion of P2x7, a receptor predominantly localised on microglia regulating release of IL-1β. This cytokine is associated with depression, bipolar disorder, and heightened aggression. P2X7 KO reduced aggression in mice, however this did not coincide with changes to microglial cell densities. P2X7 receptor deletion also decreased obsessive-compulsive behaviours, often a co-morbid diagnosis with PTSD. The P2X7 receptor, therefore, may serve as a novel target for serenic therapeutics for treatment of PTSD arousal and reactivity.