The Impact of Impaired Cyclooxygenase-2 Activity on Mouse Brain Development: A Focus on Sex Differences

There is a clear male bias in the prevalence of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Certain environmental factors have been shown to contribute to the etiology of these NDDs, including exposure to antipyretic drugs. Using cyclooxygenase-2 (COX-2) knockin and COX-2 knockout mice, genetic models which mimic exposure to antipyretic drugs, impaired COX-2 activity was found to induce sex-dependent changes in the expression of various neuroimmune markers in the brain during development. Further investigations also suggested that distinct subtypes of astrocytes may be dysregulated in male and female COX-2 knockin mice, with males exhibiting an increased prevalence of neurotoxic A1 astrocytes, and females exhibiting an increased prevalence of neuroprotective A2 astrocytes. A greater understanding of the sex-dependent effects of antipyretic drugs may ultimately facilitate the discovery of novel therapeutic targets for NDDs exhibiting a male bias, such as ASD and ADHD.