ACE2 gene transgenesis enhances memory of psychophysiological trauma in mouse models of post-traumatic stress disorder

Introduction. The development of symptoms in post-traumatic stress disorder (PTSD) is determined by a set of factors, which are not limited to classical neurotransmitter systems in the brain or stress hormones. In particular, the brain renin-angiotensin-aldosterone system may be involved in the mechanisms of PTSD. Objective. To study the effect of hACE2 expression, angiotensin-converting enzyme 2 (ACE2) gene, on anxiety and susceptibility to psycho-physiological stress in mice in the foot electroshock (FS) model of PTSD. Materials and methods. The experiments were conducted using 4–5-month-old male C57Bl/6N and k18-hACE2-KI mice. C57Bl/6N mice were divided into three groups: control ( n = 7); the foot shock (FS) ( n = 7); FS + lisinopril ( n = 7). k18-hACE2-KI mice were divided into two groups: control ( n = 7) and the FS ( n = 8). Pavlovian fear conditioning was performed using FS as an unconditioned stimulus. Mice in the FS + lisinopril group received lisinopril at a dose of 10 mg/kg per day with drinking water for 28 days after psychophysiological trauma. The expression of fear, reflecting the memory of psychophysiological trauma, was assessed on day 7 and day 28 after FS exposure. The magnitude of the fear response was assessed by evaluation of the relative time of freezing. The open field test was used to assess general locomotor activity. The tail suspension test was used to assess the stress-coping strategy, while the light-dark box test and the elevated plus maze test were used to measure anxiety. The Barnes maze test was used to explore spatial navigation and spatial learning dynamics. Behavior was analyzed using the ANY-maze Video-Tracking Software. Statistical analysis was performed using the Prism GraphPad v.10.0 software. Results. k18-hACE2-KI mice with expression of humanized ACE2 gene under the control of the cytokeratin gene promoter showed a more pronounced ability to remember and retain the memory about the conditioned stimulus/context of the traumatic event in the PTSD-model when compared to C57Bl/6N mice. Anxiety measured in the light-dark box test was lower in k18-hACE2 mice than C57Bl/6N mice after FS. At the same time, there was a decrease in the open-field motor activity and there were no changes in spatial memory in the Barnes maze test. Lisinopril, an ACE inhibitor (28 days after FS), did not reduce traumatic memory in C57Bl/6N mice, indicating that the promnestic effect of hACE2 gene expression is not a result of systemic hypotension and pointing at the involvement of the central mechanisms in the realization of hACE2 gene effect in the pathological phenotype development. Conclusions. The data indicate that the hACE2 gene affects the stress response in mice. Specifically, the expression of hACE2 gene in mice leads to increased memory of psychophysiological trauma and reduced extinction of traumatic memory compared to wild-type mice. This may be due to the modulation of the ACE2-dependent renin-angiotensin-aldosterone system in the brain. The decreased RAAS activity under the action of the ACE inhibitor lisinopril with a hypotensive effect did not affect memory in wild-type mice.