Genetic changes linked to two different syndromic forms of autism enhance reinforcement learning in early adolescent male but not female mice

Abstract Autism Spectrum Disorder (ASD) is characterized by restricted and repetitive behaviors and social differences, both of which may manifest, in part, from underlying differences in corticostriatal circuits and reinforcement learning. Here, we investigated reinforcement learning in developing mice with mutations in either Tsc2 or Shank3 , both high-confidence ASD risk genes associated with major syndromic forms of ASD. Using an odor-based two-alternative forced choice (2AFC) task, we tested early adolescent mice of both sexes and found male Tsc2 and Shank3B heterozygote (Het) mice showed enhanced learning performance compared to their wild type (WT) siblings. No gain of function was observed in females. Using a novel reinforcement learning (RL) based computational model to infer learning rate as well as policy-level task engagement and disengagement, we found that the gain of function in males was driven by an enhanced positive learning rate in both Tsc2 and Shank3B Het mice. The gain of function in Het males was absent when mice were trained with a probabilistic reward schedule. These findings in two ASD mouse models reveal a convergent learning phenotype that shows similar sensitivity to sex and environmental uncertainty. These data can inform our understanding of both strengths and challenges associated with autism, while providing further evidence that sex and experience of uncertainty modulate autism-related phenotypes. Significance Statement Reinforcement learning is a foundational form of learning that is widely used in behavioral interventions for autism. Here, we measured reinforcement learning in developing mice carrying genetic mutations linked to two different syndromic forms of autism. We found that males showed strengths in reinforcement learning compared to their wild type siblings, while females showed no differences. This gain of function in males was no longer observed when uncertainty was introduced into the reward schedule for correct choices. These findings support a model in which diverse genetic changes interact with sex to generate common phenotypes underlying autism. Our data further support the idea that autism risk genes may produce strengths as well as challenges in behavioral function.