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

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. Significant Statement We examined whether the supramammillary nucleus (SuM) is altered in mouse models with impaired social novelty recognition. In control mice, exposure to a novel conspecific robustly induced c-Fos expression in the SuM, hippocampal CA2, and dentate gyrus (DG), whereas maternal separation (MS) and Caps2 -/- mice showed reduced activation in these regions. The two models also exhibited divergent changes in SuM GPR54 expression, with reduced expression in MS mice and increased numbers of GPR54-expressing cells in Caps2 -/- mice. These findings suggest that impaired social novelty recognition is associated with reduced SuM, CA2, and DG activation across distinct models and that altered GPR54 expression may reflect model-specific molecular abnormalities linked to different etiologies.