The gene PTCHD1 is mutated in about 1% of human patients suffering from intellectual disability and autism spectrum disorders, and PTCHD1 deletion is associated with attention-deficit hyperactivity disorder (ADHD). To bridge the gap between this gene and ensuing behavioral deficits, a group led by Guoping Feng (Massachusetts Institute of Technology, Cambridge, MA) and Michael Halassa (New York University, NY) examined the effects of deleting Ptchd1 in a transgenic mouse model (Nature 532, 58–63; 2016). Their experiments uncover several important aspects of the role of this gene in a small brain structure, the thalamic reticular nucleus (TRN), in neurodevelopmental syndromes related to ADHD.

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The PTCHD1 gene encodes a transmembrane protein that is believed to act as a membrane receptor. The research team discovered that, during early development, Ptchd1 is expressed selectively in the mouse TRN, which regulates neuronal activity between the thalamus and cortex. In order to study the effects of Ptchd1 deletion, the researchers created mice that lacked a functional Ptchd1 gene, and examined neuronal and behavioral effects of this manipulation.

When neuronal recordings in the TRN were compared between Ptchd1-knockout mice and control mice, the researchers found a significant reduction in repetitive bursting activity, a reduction in intracellular calcium, abnormal sleep-related activity, and altered responses to visual stimuli. These findings suggest a strong role for Ptchd1 in normal and stable TRN activity. In addition to these neural deficits, the Ptchd1-knocokout mice exhibited hyperactivity and weaker performance on a task involving attention. The researchers performed further experiments to restrict Ptchd1 deletions primarily to the TRN, providing convincing evidence that the altered attention of the knockout animals was the result of dysfunctional TRN activity and not a loss of Ptchd1 in other brain regions.

Importantly, the team of researchers attempted to rescue the aberrant neuronal activity by applying a drug that they hypothesized could mitigate the changes observed in the TRN. After drug injection, Ptchd1-knockout mice no longer exhibited hyperactivity and showed improved performance on an attention-based task in the presence of distractors. The results of this study provide a potential molecular pathway for future studies and treatment in humans afflicted with attention disorders.