Haploinsufficiency ofShank3in Mice Selectively Impairs Target Odor Recognition in Novel Background Odors

Abstract

Individuals with mutations in a single copy of the SHANK3 gene present with social interaction deficits. Although social behavior in mice depends on olfaction, mice with mutations in a single copy of theShank3gene do not have olfactory deficits in simple odor identification tasks (Drapeau et al., 2018). Here, we tested olfaction in mice with mutations in a single copy of theShank3gene (Peça et al., 2011) using a complex odor task and imaging in awake mice. Average glomerular responses in the olfactory bulb ofShank3B+/−were correlated with WT mice. However, there was increased trial-to-trial variability in the odor responses forShank3B+/−mice. Simulations demonstrated that this increased variability could affect odor detection in novel environments. To test whether performance was affected by the increased variability, we tested target odor recognition in the presence of novel background odors using a recently developed task (Li et al., 2023). Head-fixed mice were trained to detect target odors in the presence of known background odors. Performance was tested using catch trials where the known background odors were replaced by novel background odors. We compared the performance of eightShank3B+/−mice (five males, three females) on this task with six WT mice (three males, three females). Performance for known background odors and learning rates were similar betweenShank3B+/−and WT mice. However, when tested with novel background odors, the performance ofShank3B+/−mice dropped to almost chance levels. Thus, haploinsufficiency of theShank3gene causes a specific deficit in odor detection in novel environments. Our results are discussed in the context of otherShank3mouse models and have implications for understanding olfactory function in neurodevelopmental disorders.SIGNIFICANCE STATEMENTPeople and mice with mutations in a single copy in the synaptic gene Shank3 show features seen in autism spectrum disorders, including social interaction deficits. Although mice social behavior uses olfaction, mice with mutations in a single copy of Shank3 have so far not shown olfactory deficits when tested using simple tasks. Here, we used a recently developed task to show that these mice could identify odors in the presence of known background odors as well as wild-type mice. However, their performance fell below that of wild-type mice when challenged with novel background odors. This deficit was also previously reported in the Cntnap2 mouse model of autism, suggesting that odor detection in novel backgrounds is a general deficit across mouse models of autism.