Kirrel3 homophilic adhesion function is required for male-directed aggression and vomeronasal acuity to urine...

The accessory olfactory system regulates social and reproductive behaviours in mice that are essential for survival. Proper function of this system depends on the accurate mapping of chemosensory information detected by vomeronasal sensory neurons (VSNs) into glomerular activation patterns. The formation of glomerular maps requires members of the Kirrel family of cell adhesion proteins, which mediate the coalescence of VSN axons into glomeruli. Disruption of Kirrel3 function, either through genetic deletion (Kirrel3^-/- ) or by impairing its homophilic interaction via a single amino acid substitution (Kirrel3^Q128A ), disrupts axonal glomerular map formation. Here, we compared the performance of the Kirrel3^Q128A mice to Kirrel3^-/- mice in behavioural assays involving social interactions. Similar to Kirrel3^-/- mice, Kirrel3^Q128A male mice exhibited reduced male-male aggression in the resident-intruder assay. Female Kirrel3^Q128A mice lacked maternal aggression, although other maternal behaviors, including pup retrieval and nesting, remained intact. Urine preference assays revealed increased detection thresholds to both male and female urine in Kirrel3^Q128A mice, indicating reduced vomeronasal sensitivity. However, response to non-social attractive and aversive odorants were unaffected. Notably, social novelty behavior was impaired in Kirrel3^-/- mice but preserved in Kirrel3^Q128A mice. Taken together, these results demonstrate that loss of Kirrel3-mediated adhesion is sufficient to recapitulate key deficits in vomeronasal function and VNO-dependent behaviors observed in Kirrel3 null mice, while selectively sparing certain aspects of social behavior.