Abstract A rising concern in Autism Spectrum Disorder (ASD) is the heightened sensitivity to stress and trauma, the potential consequences of which have been overlooked, particularly upon the severity of the ASD traits. This study investigated the predisposition to, and impact of, Post-Traumatic Stress Disorder (PTSD) in ASD. We first demonstrated a reciprocal relationship between the two disorders and revealed that exposure to a mild stressful event induces PTSD-like memory in four mouse models of ASD. We also establish an unanticipated consequence of stress in this condition, showing that the formation of PTSD-like memory leads to the aggravation of the core traits associated with ASD. Such a susceptibility to developing PTSD-like memory in ASD stemmed from hyperactivation of the prefrontal cortex and altered fine-tuning of parvalbumin interneuron firing. We show that this traumatic memory can be treated by recontextualization, reducing the deleterious effects on the core symptoms of ASD. Overall, this study reveals multi-level neurobiological mechanisms that explain the increased vulnerability to develop PTSD in ASD. It provides a framework for future examination of the impact of PTSD-like memory in autism and offers new directions toward behavioral therapeutic interventions targeting traumatic memory in ASD.

Parvalbumin Interneuron Activity Underlies Vulnerability to Post-Traumatic Stress Disorder in Autism