Targeting P2X7 mitigates neurobehavioural alterations in a mouse model of post-acute sequelae of SARS-CoV-2 infection

The COVID-19 pandemic has imposed a significant global health burden, leading to various long-term consequences, including persistent neuropsychiatric symptoms in a substantial proportion of infected individuals. This study investigates the role of the purinergic receptor P2X7 in mediating behaviour changes in a mouse model of post-acute sequelae of SARS-CoV-2 infection (PASC). We show that infection with a mouse-adapted SARS-CoV-2 strain induces anxiety- and depression-like behaviours in male mice, associated with elevated P2X7 receptor expression in the prefrontal cortex and hippocampus, as well as increased IFN-γ levels in the striatum. To assess the therapeutic potential of P2X7 antagonism, we administered the selective P2X7 antagonist JNJ 47965567 in vivo. Pretreatment with JNJ 47965567 mitigated the behavioural changes and reduced IFN-γ levels, suggesting a potential therapeutic role for P2X7 antagonists in the management of post-COVID neuropsychiatric symptoms. Our findings support the involvement of neuroinflammation in the symptoms of PASC and highlight the P2X7 pathway as a potential innovative therapeutic target for alleviating anxiety and depression in affected individuals and in other sequelae of post-viral neuropsychiatric conditions.