Acetaminophen-induced liver injury triggers short- and long-term neuroinflammation, blood–brain barrier disruption, and behavioral deficits in a genetic mouse model of autism

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a strong genetic basis, yet its etiology is not fully understood. Neuroinflammation is emerging as a critical secondary factor. Since peripheral organ injury, such as acute liver failure, can induce neuroinflammation, we aimed to investigate whether liver injury could exacerbate ASD-like phenotypes in a genetically susceptible model. We used adult (12-month-old) Shank3 −/− mice, a genetic model of ASD, and their wild-type (WT) counterparts. A single high dose of acetaminophen (APAP; 350 mg/kg) was administered intraperitoneally to induce acute liver injury. We assessed acute (24-h) and long-term (1-month) consequences on liver health, neuroinflammation, blood–brain barrier integrity, and brain edema using plasma biomarkers, immunohistochemistry, and in-vivo MRI, as well as behavioral phenotypes, including sociability, repetitive behaviors and exploration. Acutely, APAP induced severe liver damage, cerebral edema, and neuroinflammation in Shank3 −/− mice. One month later, despite liver recovery, both APAP-treated WT and Shank3 −/− mice exhibited brain edema, elevated apparent transverse relaxation (R2*) rates, and lasting neuroinflammation, evidenced by microgliosis and reactive astrocytosis. These differences were more extensive in the Shank3 −/− group. Behaviorally, this was accompanied by increased social deficits in both genotypes. Critically, only the APAP-treated Shank3 −/− mice displayed significantly increased repetitive behaviors, and reduced exploratory activity. Here, we show that transient liver injury is associated with long-term neuroinflammation, markers of blood–brain barrier disruption, and behavioral deficits. These findings demonstrate that while peripheral organ damage can induce lasting behavioral changes in healthy animals, the severity and spectrum of these deficits are exacerbated by ASD-associated genetic predisposition. These findings support a preclinical gene-environment interaction framework relevant to ASD-associated vulnerability.