Autism‐related behaviors in the cyclooxygenase‐2‐deficient mouse model

Abstract

Prostaglandin E2 (PGE2) is an endogenous lipid molecule involved in normal brain development. Cyclooxygenase-2 (COX2) is the main regulator of PGE2 synthesis. Emerging clinical and molecular research provides compelling evidence that abnormal COX2/PGE2 signaling is associated with autism spectrum disorder (ASD). We previously found that COX2 knockout mice had dysregulated expression of many ASD genes belonging to important biological pathways for neurodevelopment. The present study is the first to show the connection between irregular COX2/PGE2 signaling and autism-related behaviors in male and female COX2-deficient knockin, (COX)-2 , mice at young (4-6 weeks) or adult (8-11 weeks) ages. Autism-related behaviors were prominent in male (COX)-2 mice for most behavioral tests. In the open field test, (COX)-2 mice traveled more than controls and adult male (COX)-2 mice spent less time in the center indicating elevated hyperactive and anxiety-linked behaviors. (COX)-2 mice also buried more marbles, with males burying more than females, suggesting increased anxiety and repetitive behaviors. Young male (COX)-2 mice fell more frequently in the inverted screen test revealing motor deficits. The three-chamber sociability test found that adult female (COX)-2 mice spent less time in the novel mouse chamber indicative of social abnormalities. In addition, male (COX)-2 mice showed altered expression of several autism-linked genes: Wnt2, Glo1, Grm5 and Mmp9. Overall, our findings offer new insight into the involvement of disrupted COX2/PGE2 signaling in ASD pathology with age-related differences and greater impact on males. We propose that (COX)-2 mice might serve as a novel model system to study specific types of autism.

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

“…Overall, although not shown in this study, these SRF target genes could enhance mechanisms of neuronal inhibition during TBI and thereby limit hyperactivity related behavior. In keeping with this, mouse mutants of several of these IEGs including Egr3, Nptx2, Ptgs2, and Npas4 also induce hyperactivity suggesting a function for the wt proteins in restricting hyperactive behavior.…”

“…SRF regulates several neuronal activity encoding IEGs including Npas4, Egr ( Egr1, Egr2, Egr3 ) and Fos ( cFos, ΔFosb ) family members, pentraxins and cyclooxygenase ( Ptgs2 ). Of note, those IEGs were reported to induce hyperactivity phenotypes upon deletion in mice . In order to test whether altered regulation of such effector genes by SRF ablation might underlie TBI inflicted behavioral phenotypes we measured mRNA (Figure ) and protein (Figure ) abundance of several neuronal activity related genes.…”

“…Of note, those IEGs were reported to induce hyperactivity phenotypes upon deletion in mice. [55][56][57][58][59] In order to test whether altered regulation of such effector genes by SRF ablation might underlie TBI inflicted behavioral phenotypes we measured mRNA ( Figure 6) and protein ( Figure 7) abundance of several neuronal activity related genes.…”

Paracetamol use during pregnancy — a call for precautionary action

“…Prostaglandin E2 is an endogenous lipid molecule involved in normal brain development, regulating cerebellar development and inducing masculinization of the preoptic area of the brain 70 . Emerging clinical and molecular research has provided compelling evidence that abnormal cyclooxygenase 2 and prostaglandin E2 signalling is associated with ASD-related pathology and behaviours 68,69,154,[156][157][158] . Other data suggest that the analgesic effect of APAP acts through the endocannabinoid system 159 .…”

The neuroscience and genomics of social behavior

“…PGE2 synthesis is in turn regulated by cyclooxygenase-2 (COX2). Wong et al 18 report on a phenotype of ASD-related behaviors, including social disturbances, and associated gene expression changes, in COX2 null mutant mice. In doing so, they build upon emerging evidence linking COX2/PGE2 signaling to ASD.…”