Early Postnatal Shank3 Downregulation in the Nucleus Accumbens Impairs Performance in Social Conditioning Paradigms in Male Mice

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by reduced social interactions, as well as repetitive behaviors and restricted interests. Mutations in SHANK3 , a scaffolding protein located postsynaptically at excitatory synapses, are associated with ASD, schizophrenia, and intellectual disability in humans. Similar autism‐like phenotypes have been observed in Shank3 ‐deficient rodent models. The mesolimbic dopamine pathway appears to be particularly sensitive to Shank3 disruptions. We have previously shown that Shank3 downregulation in the nucleus accumbens (NAc) ( Shank3‐NAcKD ) during early postnatal development impaired social preference in the three‐chamber test. Here, we aimed to assess whether this Shank3 downregulation would lead to deficits in social conditioning paradigms. Specifically, using the social instrumental task (SIT), we found that Shank3‐NAcKD male mice performed fewer lever presses to gain access to social interaction with a nonfamiliar juvenile mouse. Moreover, these mice failed to develop a preference for the chamber associated with social stimuli in a conditioned place preference (CPP) task. Unsupervised analysis of locomotor motifs during CPP revealed distinct exploratory strategies, with an altered allocation of exploratory behaviors between the socially paired and unpaired chambers, suggesting a suboptimal direction of exploration towards relevant social‐associated cues. Our current data expand on our previous research to understand the involvement of mesolimbic Shank3 expression in autism‐like phenotypes. Additionally, our results underline that local Shank3 manipulation during early postnatal life leads to intricate social behavior deficits, highlighting the need for an in‐depth dissection of behavioral phenotypes in rodent models of ASD.