Circuit-level theories for sensory dysfunction in autism: convergence across mouse models

Individuals with autism spectrum disorder (ASD) exhibit a diverse range of behavioral features and genetic backgrounds, but whether different genetic forms of autism involve convergent pathophysiology of brain function is unknown. Here, we analyze evidence for convergent deficits in neural circuit function across multiple transgenic mouse models of ASD. We focus on sensory areas of neocortex, where circuit differences may underlie atypical sensory processing, a central feature of autism. Many distinct circuit-level theories for ASD have been proposed, including increased excitation-inhibition (E-I) ratio and hyperexcitability, hypofunction of parvalbumin (PV) interneuron circuits, impaired homeostatic plasticity, degraded sensory coding, and others. We review these theories and assess the degree of convergence across ASD mouse models for each. Behaviorally, our analysis reveals that innate sensory detection behavior is heightened and sensory discrimination behavior is impaired across many ASD models. Neurophysiologically, PV hypofunction and increased E-I ratio are prevalent but only rarely generate hyperexcitability and excess spiking. Instead, sensory tuning and other aspects of neural coding are commonly degraded and may explain impaired discrimination behavior. Two distinct phenotypic clusters with opposing neural circuit signatures are evident across mouse models. Such clustering could suggest physiological subtypes of autism, which may facilitate the development of tailored therapeutic approaches.

Automated summary

This study analyzed multiple transgenic mouse models of autism spectrum disorder (ASD) to investigate the convergence of deficits in neural circuit function. The findings revealed heightened innate sensory detection behavior and impaired sensory discrimination behavior across many ASD models. Neurophysiologically, hypofunction of parvalbumin (PV) interneurons and increased excitation-inhibition (E-I) ratio were prevalent, but hyperexcitability and excess spiking were rarely observed. Instead, sensory tuning and other aspects of neural coding were commonly degraded, which may explain the impaired discrimination behavior. Two distinct phenotypic clusters with opposing neural circuit signatures were evident. These findings may contribute to the development of tailored therapeutic approaches for autism.