Early life ACE2 inhibition leads to long term anxiety-like behaviour in rats by disrupting the amygdala

Angiotensin-converting enzyme 2 (ACE2) is important for cardiac and renal development as well as appropriate perinatal growth. In addition, ACE2 has recently attracted notice as the cellular entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with evidence that the downregulation of ACE2 associated with SARS-CoV-2 may be linked to its long-lasting neurological and neurocognitive effects. However, the long-term neurological consequences of early life ACE2 suppression remain unclear. Here, we hypothesized that downregulation of ACE2 would predispose juveniles to anxiety-like behaviour in adulthood. To test our hypothesis, we administered a potent and selective ACE2 inhibitor, MLN-4760, to male and female Wistar rats in the juvenile (postnatal day (P)23) or adult (P56) phases, assessing anxiety-like behaviours and neuronal outcomes later in adulthood. Our findings demonstrate that transient pharmacological inhibition of ACE2 during the juvenile period (P23) induces persistent anxiety-like and anhedonic-like behaviours in male rats, effects that are not seen in females. These behavioural changes are accompanied by a marked reduction in parvalbumin-positive inhibitory interneurons in the amygdala and an increase in synaptophysin expression in the hippocampus, suggesting a reconfiguration of excitatory-inhibitory balance within key affective circuits. Microglial number and morphological changes are also evident in the same regions. ACE2 inhibition in adulthood (P56) failed to produce similar outcomes, highlighting a sensitive developmental window. These data demonstrate that early-life ACE2 suppression could elicit long-term neuropsychiatric vulnerability, with sex-specific trajectories. These findings have relevance to childhood COVID-19, suggesting further research in this population is needed.