Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time

Lee et al. show that in male Shank3-mutant mice, mPFC neurons are impaired in encoding of social agency. Shank3 reexpression in mPFC restored this ability in real time, and this was accompanied by rescue of normal social behavior. Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD.

Automated summary

The study demonstrates that disruption of Shank3 gene in adult male mice alters the encoding dynamics of neurons in the medial prefrontal cortex (mPFC), leading to impaired social behavior. Restoration of Shank3 expression reverses this encoding imbalance, ultimately enhancing sociability. This reveals a crucial neuronal-encoding process for social behavior that may be disrupted in autism spectrum disorder (ASD).