NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder

Abstract

Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4-hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS.

A SYSTEMATIC REVIEW OF TUMOR NECROSIS FACTOR-α IN POST-TRAUMATIC STRESS DISORDER: EVIDENCE FROM HUMAN AND ANIMAL STUDIES

“…Furthermore, in both of these studies, treatment with medication resulted in a reduction in anxiety-like behaviours (as measured by the elevated plus maze test) to levels observed in non-stressed rats. Conversely, Liu et al (2016) did not find any difference in TNF-levels in the hippocampus of rats after SPS compared to nonstressed rats. No difference also observed in second assessment at one week after baseline.…”

“…Two of the studies measured TNF-levels (Levkovitz et al 2015, Liu et al 2016) and one assessed TNF-mRNA (Lee et al 2016) in the hippocampus of stressed rats. The results of these studies are presented in Table 1.…”

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder

“…Moreover, PV-positive GABAergic interneurons are closely linked to fear memory [27], which is also supported by our previous study [13].…”

“…It has been reported that aversive foot shocks inhibit PV interneuron function, which reinforces postsynaptic foot shock responses and gates learning [12]. Consistently, our previous study has also demonstrated that phenotype loss of PV interneurons can elicit abnormal behaviors in a rat model of PTSD induced by single-prolonged stress [13]. These findings suggest that phenotype loss of PV interneurons and behavioral impairments associated with PTSD are casually linked.…”

“…In particular, NOX2-derived ROS production plays a critical role in GABAergic interneurons dysfunction after subchronic ketamine repetitive exposure in mice [35]. Also, the role of oxidative damage as a key factor in the development of PTSD has been implicated, because reversing the overproduced ROS is able to improve symptoms in an animal model of PTSD [13]. In our study, we showed that 8-OH-dG was significantly up-regulated by IFS.…”