THE NEUROLIGIN-3 R451C VARIANT IMPACTS INFLAMMATORY RESPONSES: SEX-SPECIFIC RESILIENCE FOLLOWING DSS-INDUCED COLITIS IN A MOUSE MODEL OF AUTISM

Children with autism frequently experience gastrointestinal symptoms and inflammatory disorders, including ulcerative colitis; but differences in immune responses or behavioural outcomes are unclear. Using the well-established dextran-sodium-sulfate (DSS) model of colitis, we assessed disease progression and behavioural outcomes during active inflammation and recovery in a mouse model of autism. Adult male and female Nlgn3^R451C mice expressing an autism-associated variant in the Neuroligin-3 synaptic protein received 2%-DSS for 7 days prior to recovery during 2-weeks. Mice were monitored using the daily disease activity index (DAI). Locomotion and anxiety-like behaviours were assessed via open field (OF) every other day from day 7-21. DSS-treated Nlgn3^R451C female mice had lower DAI scores, and colitis symptoms compared to WT-males at day 7(5±1.2 vs 8.6±0.4, p=0.002). OF tests(2 and 4-days after DSS-treatment) revealed reduced mobility in DSS-treated WT-males compared to SHAM(2-days:19.2±2 vs 33.7±3m,p=0.007; 4-days: 19±3 vs 32.2±3m,p=0.04), but not in WT-female mice 2-days:24.2±4 vs 27±2m,p=0.6; 4-days: 24.2±3 vs 34.8±1m,p=0.07). One week post DSS-treatment, WT but not Nlgn3^R451C DSS-treated male mice spent more time in the OF centre zone compared to SHAM males(4.3±2 vs 17.7±4% total time, p=0.002). Female Nlgn3^R451C mice show resilience to DSS-induced colitis compared to WTs. Locomotor impairments during active colitis reflect sickness behaviour, whereas increased time in the OF centre during recovery suggests that inflammation differentially affects behaviour in male Nlgn3^R451Cand WT mice. Further assessment of neuro-immune markers is needed to understand potential roles of Nlgn3^R451C on long-term colitis-related sickness behaviour