Subcortical circuit dysfunctions delay perceptual decision-making in autism models

Abstract

Autism spectrum disorders (ASD) include a range of neurodevelopmental conditions characterised by social and communication difficulties1, often co-occurring with sensory processing abnormalities2. The neural origins of these impairments are thought to reside in cortical circuits3–5. Here we demonstrate that a subcortical node required to initiate efficient and timely responses to visual threats is disrupted across genetic models of ASD. Although mutant mice can detect visual threat stimuli, they require longer to evaluate them and respond with less vigour than their wild-type siblings. These delays in perceptual judgement are linked to reduced place-aversion to visual threats. Visual responses and other motor properties remain unaffected, overall indicating cognitive rather than sensory or motor impairments. Focusing on one of the models (Setd5), we show that these behavioural deficits are recapitulated following optogenetic activation of excitatory deep medial collicular neurons, known to initiate threat responses by exciting the dorsal periaqueductal grey (dPAG). Consistently,ex vivopatch-clamp recordings ofSetd5mutant dPAG neurons revealed a stark hypoexcitability phenotype mediated by misregulation of a voltage-gated potassium channel. Similar physiological characterisation across ASD models demonstrates that different molecular mechanisms converge on similar behavioural phenotypes. Our results show that the timing of perceptual decision-making is regulated via intrinsic excitability and emphasise the use of an innate behaviour to mechanistically dissect cognitive disorders.