Mike (Wells) and Ralf’s paper just got published in Nature as an article. This is a collaboration with Guoping Feng’s lab at MIT, and likely one of a series of studies that clarifies that circuit basis of several neuropsychiatric and neurodevelopmental disorders. In this paper, we show that the attention deficit and hyperactivity (ADHD symptoms) in a mouse model of human neurodevelopmental disease are explained by TRN (thalamic reticular nucleus) dysfunction.
PTCHD1 deletion in humans is associated with autism, ADHD and intellectual disability. The children afflicted with this developmental disease experience a wide range of symptoms, including attention deficit, hyperactivity, aggression, hypotonia, sleep perturbation and learning disability. PTCHD1 deletion mice capture all of these symptoms, validating their usefulness as a model of this human genetic variant. Taking full advantage of the mouse’s experimental accessibility, we determined that the ADHD symptoms and sleep perturbation (but not everything else) are explained by TRN malfunction in the PTCHD1 deletion mice. We were led down that path by finding that PTCHD1 is selectively expressed in the TRN during early postnatal development. Selective deletion of PTCHD1 from the TRN recaptured the ADHD and sleep symptoms, and pharamcological reversal of TRN dysfunction partially recovered these symptoms selectively. Overall, we provide a putative circuit mechanism for attention deficits and sensory overload symptoms in one form of human autism/ADHD. We call it the leaky thalamus, and think that it might be a common circuit basis for attention deficit and sensory overload across several neurodevelopmental diseases.
Our work is in line with the Research Domain Criteria (RDoC) scheme of mental illness, which suggest that going after core biological mechanisms that may cut across several diagnostic categories is likely a more fruitful way of understanding and treating neurodevelopmental diseases than focusing on arbitrary disease categories. We think that the leaky thalamus is an identified core mechanism.
Congrats to Mike and Ralf on this wonderful achievement!