The subjective experience of internal sensation processing (interoception) which affects emotions, appears to be altered in autism spectrum disorder (ASD) and anxiety disorders. Anxiety is a frequently co-occurring condition in patients with ASD, exacerbating ASD symptoms and causing functional impairments in these individuals. In contrast to anxiety in normotypic populations, our knowledge about the neuronal correlates of anxiety in ASD is very limited. Here we investigated behavioral responses to CO2 inhalation in Setd5 haploinsufficient (Setd5+/-) mice, which demonstrate signs of ASD and altered anxiety-related behavior, as compared with their wildetype littermates. Inducing hypercapnia is a highly translational, RDoC recommended, paradigm known to activate interoception and trigger anxiety in different species from mice to humans. Exposure to CO2 decreased locomotion and exploratory behaviors and increased anxiety-related parameters in both lines as compared with air control condition. Relative to air, CO2-induced behavioral changes were more pronounced in Setd5+/- than in wildtype controls with sex-specific differences. To identify neuronal substrates underlying these differences, immediate early gene expression as a marker for neuronal activation is currently investigated in these CO2-exposed subjects. The first results point towards altered activation of the paraventricular hypothalamic nucleus and the insula. Overall, CO2 inhalation is suggested to be an interesting paradigm for studying neurobiological mechanisms underlying the altered processing of interoceptive stimuli in ASD.