Reticular thalamic hyperexcitability drives autism spectrum disorder behaviors in the Cntnap2 model of autism

Abstract

Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Although thalamocortical circuit dysfunction has been implicated in these symptoms, its precise roles in ASD pathophysiology remain poorly understood. Here, we examine the specific contribution of the reticular thalamic nucleus (RT), a key modulator of thalamocortical activity, to ASD-related behavioral deficits using a Cntnap2 knockout mouse model. Cntnap2^−/− mice displayed increased seizure susceptibility, locomotor activity, and repetitive behaviors. Electrophysiological recordings revealed enhanced intrathalamic oscillations and burst firing in RT neurons, accompanied by elevated T-type calcium currents. In vivo fiber photometry confirmed behavior-associated increases in RT population activity. Notably, pharmacological and chemogenetic suppression of RT excitability via Z944, a T-type calcium channel blocker, and via C21 activation of the inhibitory DREADD hM4Di significantly improved ASD-related behaviors. These findings identify RT hyperexcitability as a mechanistic driver of ASD and highlight RT as a potential therapeutic target.