Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/-) mice.

Abstract

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect 1 in 6 children in the United States. Recently, PTCHD1 (Patched-domain containing protein 1) gene mutations have been found in ~1% of patients with ID and ASD. PTCHD1 deletion patients show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is likely critical for normal development, the connection between its deletion and the ensuing behavioral defects is poorly understood. Here, we report that during early postnatal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamo-cortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity by reducing calcium-dependent potassium currents (SK). Restricted TRN deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channels. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically-relevant behavioral phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.