title: 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 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.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.|McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wells
authors.affiliation: Neuroscience Institute, New York University Langone Medical Center, New York, New York 10016, USA.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: Ralf D
authors.initials: RD
authors.lastname: Wimmer
authors.affiliation: Neuroscience Institute, New York University Langone Medical Center, New York, New York 10016, USA.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016, USA.
authors.forename: L Ian
authors.initials: LI
authors.lastname: Schmitt
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.affiliation: Neuroscience Institute, New York University Langone Medical Center, New York, New York 10016, USA.|Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016, USA.|Department of Psychiatry, New York University Langone Medical Center, New York, New York 10016, USA.|Center for Neural Science, New York University, New York, New York 1003, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Halassa
mesh_terms: D000374:Aggression; D000818:Animals; D000831:Animals, Newborn; D001288:Attention; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology*; D001522:Behavior, Animal; D004195:Disease Models, Animal; D004553:Electric Conductivity; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D007859:Learning Disabilities / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000068079:Motor Disorders / Q000235:genetics / Q000503:physiopathology; D009433:Neural Inhibition; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D012890:Sleep; D012892:Sleep Deprivation / Q000235:genetics / Q000503:physiopathology; D013787:Thalamic Nuclei / Q000473:pathology / Q000503:physiopathology*
chemical_list: D008565:Membrane Proteins; D024681:Potassium Channels, Calcium-Activated; C000607337:Ptchd1 protein, mouse