Monday, April 11, 2016

ADHD and the leaky thalamus

Wells MF, Wimmer RD, Schmitt LI, Feng G, Halassa MM. Thalamic reticular
impairment underlies attention deficit in Ptchd1(Y/-) mice. Nature. 2016 Mar 23.
doi: 10.1038/nature17427. [Epub ahead of print]


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.

The co-authors also suggested that their findings could eventually lead to a new disease category that includes the autism spectrum and intellectual disability as well as ADHD. “To our knowledge, this is the first study to detail the biology behind thalamic dysfunction in cognitive disorders…,” said senior investigator Michael M. Halassa MD, PhD, an assistant professor of neuroscience at NY Langone. “We believe that this work defines a new disease category based on common biological signatures….”

In their research on what they called a “leaky thalamus,” the scientists looked at what happens when a specific gene, Ptchd1, is deleted to genetically alter mice. The scientists found that Ptchd1 plays a role in modulating the amount of SK (small conductance calcium-dependent potassium currents) that help the thalamus communicate with other parts of the brain and inhibit inattention and hyperactivity

Mice without Ptchd1 made three times as many concentration errors in concentration tests as unaltered mice and had difficulties screening out distractions, the study said. These mice also were insensitive to treatment with stimulants, the study added, which suggested that the ADHD in the people who don’t respond to stimulants may have a disorder with a different origin. The authors noted that “ADHD symptoms are frequently observed in patients with Ptchd1 mutations.”

The researchers did have success in improving the thalamus signaling in the genetically altered mice with the drug 1-ethyl-benzimidazolinone, but said it’s not useable humans. Nonetheless, the effectiveness of that drug suggested that scientists should look for a medication that has the same effect on humans, the authors added.


  1. Torrico B, Fernàndez-Castillo N, Hervás A, Milà M, Salgado M, Rueda I, Buitelaar JK, Rommelse N, Oerlemans AM, Bralten J, Freitag CM, Reif A, Battaglia A, Mazzone L, Maestrini E, Cormand B, Toma C. Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability. Eur J Hum Genet. 2015 Dec;23(12):1694-701.


    Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P=6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P=0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P=7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P=0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P=0.003, permP=0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder.

  2. Chaudhry A, Noor A, Degagne B, Baker K, Bok LA, Brady AF, Chitayat D, Chung BH, Cytrynbaum C, Dyment D, Filges I, Helm B, Hutchison HT, Jeng LJ, Laumonnier F, Marshall CR, Menzel M, Parkash S, Parker MJ; DDD Study, Raymond LF, Rideout AL, Roberts W, Rupps R, Schanze I, Schrander-Stumpel CT, Speevak MD, Stavropoulos DJ, Stevens SJ, Thomas ER, Toutain A, Vergano S, Weksberg R, Scherer SW, Vincent JB, Carter MT. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations ncludes intellectual disability and autism spectrum disorder. Clin Genet. 2015 Sep;88(3):224-33.


    Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.