Age-dependent cortical overconnectivity revers under anesthesia in Shank3 mice

Abstract

ABSTRACTIncreasing evidence points to brain network dysfunction as a central neurobiological basis for autism spectrum disorders (ASDs). Consequently, studies on Functional Connectivity (FC) have become pivotal for understanding autism-related large-scale network dynamics. While autism is a neurodevelopmental disorder, existing FC studies in mouse models largely focus on adult subjects under anesthesia. Given that FC can be significantly influenced by brain state, the differential impact of anesthesia on cortical functional networks in autistic subjects remains unexplored. To fill this gap, we conducted a longitudinal evaluation of FC across three distinct brain states in the Shank3b mouse model of autism. We utilized wide-field calcium imaging to monitor cortical activity in Shank3b+/-and Shank3b+/+mice from late development through adulthood, and isoflurane anesthesia to manipulate the brain state. Our findings reveal that network hyperconnectivity, initially evident in the barrel-field cortices during the juvenile stage, progressively expands to encompass the entire dorsal cortex in adult Shank3b+/-mice. Notably, the severity of FC imbalances is highly dependent on the brain state: network alterations are more pronounced in the awake state and shift towards hypoconnectivity under anesthesia. These results underscore the crucial role of anesthesia in detecting autism-related FC alterations and identify a significant network of early cortical dysfunction associated with autism. This network represents a potential target for non-invasive translational treatments.