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Nature DOI:10.1038/nature17427

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

Publication TypeJournal Article
Year of Publication2016
AuthorsWells, MF, Wimmer, RD, L Schmitt, I, Feng, G, Halassa, MM
Date Published2016 Apr 07
KeywordsAggression, Animals, Animals, Newborn, Attention, Attention Deficit Disorder with Hyperactivity, Behavior, Animal, Disease Models, Animal, Electric Conductivity, Female, GABAergic Neurons, Gene Deletion, Humans, Learning Disorders, Male, Membrane Proteins, Mice, Mice, Knockout, Motor Disorders, Neural Inhibition, Potassium Channels, Calcium-Activated, Sleep, Sleep Deprivation, Thalamic Nuclei

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ~1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. 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 behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.


Alternate JournalNature
PubMed ID27007844
PubMed Central IDPMC4875756
Grant ListR01MH097104 / MH / NIMH NIH HHS / United States
R01 MH097104 / MH / NIMH NIH HHS / United States
R01 MH107680 / MH / NIMH NIH HHS / United States
R01MH10768 / MH / NIMH NIH HHS / United States
R00 NS078115 / NS / NINDS NIH HHS / United States
F31 MH098641 / MH / NIMH NIH HHS / United States