Odor experience stabilizes glomerular output representations in two mouse models of autism

Novel stimuli can be stressful for individuals with Autism Spectrum Disorders (ASD), though repeated exposure can reduce this effect. In Cntnap2 -/- and Shank3B +/- mouse models of ASD, novel background odors impaired behavioral target odor recognition but that deficit improved with training. To investigate the neural basis of this improvement, we used widefield calcium imaging to measure olfactory bulb responses in Cntnap2 -/- and Shank3B +/- mice and WT mice of either sex. Training with background odors enhanced both behavioral performance and neural discriminability of odor mixtures in both Cntnap2 -/- and Shank3B +/- as well as WT mice. Naïve Cntnap2 -/- and Shank3B +/- mice showed greater trial-to-trial neural variability than WT mice, but training stabilized neural responses. Critically, training produced a widespread reduction in olfactory bulb responses to background odors in ASD models, but not in WT mice. Thus, despite similar behavioral improvements as WT mice, Cntnap2 -/- and Shank3B +/- mice relied on a distinct broad suppression of background odor responses to enhance olfactory coding in the presence of background odors. Significance Statement Abnormal sensory responses to unfamiliar stimuli are a hallmark of Autism Spectrum Disorders (ASD) and can be alleviated with prolonged exposure. Neural variability in sensory responses is observed in both individuals with ASD and different mouse models, but its impact on behavior remains unclear. Using two ASD-associated gene mutation models ( Shank3 and Cntnap2 ), we performed widefield calcium imaging in the olfactory bulb. Prolonged exposure to a background odor stabilized olfactory bulb activity, enhancing neural coding and discrimination in these two different mouse models of ASD, but not in WT mice, despite similar improvements in behavior. This work highlights how neural activity fluctuations in the olfactory bulb influence behavior in ASD, offering insights into sensory processing mechanisms and potential therapeutic strategies.