Abnormal Microglial Density and Morphology in the Brain of Cyclooxygenase 2 Knockin Mice

Prostaglandin E2 (PGE2) is a signaling molecule produced by cyclooxygenase-2 (COX-2) that is important in healthy brain development. Anomalies in the COX-2/PGE2 pathway due to genetic or environmental factors have been linked to Autism Spectrum Disorders (ASD). Our previous studies showed that COX-2 deficient (COX-2^-KI) mice exhibit sex-dependent molecular changes in the brain and associated autism-related behaviors. Here, we aim to determine the effect of COX-2^-KI on microglial density and morphology in the developing brain. Microglia normally transition between an amoeboid or ramified morphology depending on their surroundings and are important for the development of the healthy brain, assisting with synaptogenesis, synaptic pruning, and phagocytosis. We use COX-2^-KI male and female mice to evaluate microglia density, morphology, and branch length and number in five brain regions (cerebellum, hippocampus, olfactory bulb, prefrontal cortex, and thalamus) at the gestational day 19 (G19) and postnatal day 25 (PN25). We discovered that COX2^-KI females were affected at G19 with increased microglial density, altered percentage of amoeboid and ramified microglia, affected branch length, and decreased branching networks in a region-specific manner; these effects persisted to PN25 in select regions. Interestingly, while limited changes were found in G19 COX-2^-KI males, at PN25 we found increased microglial density, higher percentages of ramified microglia, and increased branch counts, and length observed in nearly all brain regions tested. Overall, we show for the first time that the COX-2 deficiency in our ASD mouse model influences microglia morphology in a sex- and region- and stage-dependent manner.