P1.157: Gasdermin D Modulates Sex-specific Social Interbehavior Abnormalities in Mice

Background: Prematurity is a major risk factor for neurodevelopmental disorders, including autism spectrum disorder (ASD), which disproportionately affects males. Cerebellar abnormalities, particularly Purkinje cell dysfunction, are strongly linked to ASD pathology. While Purkinje cell dysfunction is a hallmark of ASD, controlled developmental cell loss is a normal process shaping neural circuits. Emerging evidence suggests that Gasdermin D (GSDMD), a key pyroptotic effector, can be activated by the Aim2 inflammasome in response to DNA damage and plays a role in programmed neuronal cell loss. Dysregulation of this pathway may contribute to aberrant neurodevelopment, leading to sex-specific behavioral and social impairments. Accumulation of DNA damage in Purkinje cells may further exacerbate these effects, disrupting cerebellar function. The aim of this study is to determine the role of GSDMD in the development of sex-specific behavioral and social interaction impairments. By investigating GSDMD-mediated developmental cell loss and its impact on cerebellar circuits, we seek to elucidate its contribution to ASD risk and the male bias observed in neurodevelopmental disorders. Understanding this mechanism could reveal novel therapeutic targets for early intervention in ASD and other neurodevelopmental disorders associated with prematurity.

Methods: Neurobehavioral tests were conducted on male and female C57BL/6 wild-type (WT) and gasdermin D knockout (GSDMD KO) mice at 2–4 months of age. The behavioral assessment included the three-chamber test for social interaction, the open-field test for anxiety-related and stereotypical behaviors, the rotarod for motor coordination, and the Barnes maze for memory. This report focuses on the three-chamber and open-field tests. The data was analyzed by two-way ANOVA with a value considered significant for P less than 0.05. Following behavioral assessments, brain tissue was collected for molecular and histological analyses.

Results: At 2–4 months of age, GSDMD KO male mice, but not females, exhibited impaired social interaction, as evidenced by reduced interaction time with stranger mice in the three-chamber test (Figure 1a). In the open-field test, GSDMD KO males displayed a significant increase in the number and duration of stereotypical behaviors (Figure 1c,d) and reduced ambulatory counts compared to WT males (Figure 1d). No significant differences were observed between WT and GSDMD KO mice in total ambulatory time, distance traveled, velocity, jump counts, or jump duration. Additional behavioral testing and histological analysis are ongoing.

Conclusion: GSDMD KO male mice exhibited sex-specific behavioral abnormalities, including impaired social interaction and increased stereotypical behaviors, consistent with phenotypes observed in ASD. These findings suggest that GSDMD may contribute to the male bias observed in ASD and other neurodevelopmental disorders associated with prematurity.