Lihao Sun Nobuhiko Ohashi Takuma Mori Yuka Mizuno Weichen Zang Qi Guo Emi Kouyama-Suzuki Yoshinori SHIRAI Katsuhiko Tabuchi ^*

• Shinshu University, Matsumoto, Japan

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and communication, along with restricted and repetitive behaviors. Both genetic and environmental factors contribute to ASD, with prenatal exposure to valproic acid (VPA) and nicotine being linked to increased risk. In this study, we investigated social behavior and adult neurogenesis in C57BL/6J mice prenatally exposed to VPA or nicotine, as well as in genetically modified ASD models, including IQSEC2 knockout (KO) and NLGN3-R451C knock-in (KI) mice. We employed a three-chamber social interaction test to evaluate sociability and social novelty preference. VPA-exposed mice displayed significant social interaction deficits, whereas nicotine-exposed mice exhibited mild impairment in social novelty preference. In addition, both ASD model groups demonstrated a reduction in adult neurogenesis, specifically within the ventral hippocampus, a region associated with social behavior and emotion. Further, we assessed adult hippocampal neurogenesis using BrdU and DCX immunofluorescence to identify newborn and immature neurons. A significant decrease in BrdU+/NeuN+ cells was observed in the ventral hippocampus across all ASD mouse models, whereas dorsal hippocampal neurogenesis was relatively unaffected. Similar reductions in DCX-positive cells were noted in VPA, nicotine, and NLGN3-R451C mice, indicating impaired proliferation or differentiation of neuronal progenitors. These findings suggest that impaired adult neurogenesis in the ventral hippocampus may be a common hallmark across ASD mouse models, potentially underlying social behavior deficits. This study provides insight into regionspecific neurogenic alterations linked to ASD pathophysiology and highlights potential targets for therapeutic interventions.