Reduced SuM Activation Accompanies Impaired Social Novelty Recognition in Mouse Models of Neurodevelopmental...

Social novelty recognition-the ability to distinguish between familiar and unfamiliar individuals-is frequently disrupted in neurodevelopmental disorders, including those resulting from early-life stress and autism spectrum disorder (ASD). The supramammillary nucleus (SuM) has been implicated as a key region involved in processing novelty-related information and associated with hippocampal CA2 activity; however, whether SuM dysfunction occurs in neurodevelopmental disorder models with impaired social novelty recognition remains unclear. Here, we examined c-Fos expression in the SuM, CA2, and dentate gyrus (DG) following exposure to a novel conspecific in male mice from two models: maternal separation (MS) mice representing early-life stress and Caps2^-/- mice, a genetic model of ASD. Novel social encounters robustly induced c-Fos expression in the SuM, dorsal and ventral CA2, as well as dorsal and ventral DG regions in control mice, whereas such induction was not observed in either MS or Caps2^-/- mice. Furthermore, GPR54 expression in the SuM differed between the two models, with MS mice showing reduced expression, whereas Caps2^-/- mice exhibited an increased number of GPR54-expressing cells. These findings suggest that reduced activation of the SuM, CA2, and DG is a shared feature across distinct models with impaired social novelty recognition. Furthermore, the divergent patterns of GPR54 expression raise the possibility that KISS1-GPR54 signaling may differentially modulate SuM function across models, although its causal role remains to be determined.