Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Thalamic Inhibition Impairment Underlies Autism Spectrum Disorders (ASD)


Nature  532, 58–63 (07 April 2016)

Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice

Michael F. Wells,

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

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

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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


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.

Recent genetic studies have revealed substantial overlap of risk genes across seemingly distinct neurodevelopmental and psychiatric disorders including ASD, ADHD, schizophrenia, and ID. Such shared genetic architectures could potentially explain the overlap of behavioural abnormalities across these diagnostic categories, but because of the difficulty in mapping circuitry mechanisms of behaviour, understanding how diverse genetic lesions converge onto behaviour-relevant circuit dysfunction has been limited.

Here we focused on PTCHD1, a gene that is mutated in about 1% of all patients with ASD and ID. Comprehensive clinical analysis of PTCHD1 deletion patients identified a variable non-syndromic neurodevelopmental disorder with symptoms ranging from attention deficit, hyperactivity, sleep abnormality, hypotonia, and learning disability. We found that Ptchd1 was selectively expressed in the TRN of mice in early development and continued to be enriched in this structure throughout adult life. The TRN is critical for thalamocortical transmission, generation of sleep rhythm, sensorimotor processing, and attention, and its perturbation could result in deficits in these domains. By generating a conditional Ptchd1-knockout mouse, we mapped ADHD-like behaviours onto TRN circuit dysfunction via two independent methods. First, by deleting Ptchd1 selectively from the TRN, we replicated the attention deficit and hyperactivity behaviours, but not other disease-related phenotypes found in the full knockout. Second, pharmacological rescue of TRN biophysical dysfunction selectively rescued these ADHD-related behaviours in the Ptchd1 knockout. These findings constitute the first evidence for a ‘leaky thalamus’ in a neurodevelopmental disorder, where irrelevant inputs that are normally suppressed become highly distracting. Most importantly, we identified the TRN and its SK channels as circuit and molecular targets for intervention.

Previous studies have suggested that TRN bursting plays a role in the generation of sleep spindles, predicting that the diminished bursting found in Ptchd1-knockout mice would lead to reduced sleep spindles. Using independently adjustable multi-electrode arrays to directly target TRN neurons for electrophysiological recordings in freely behaving animals and surface electroencephalography, we discovered that TRN neurons from knockout mice exhibited reduced burst firing in sleep and knockout mice showed an overall reduction in sleep spindle count. Further, the degree of TRN neuronal engagement in spindle events was substantially diminished in the knockout, supporting the link between the cellular and network phenotypes in this disorder and perhaps other human neurodevelopmental disorders. Importantly, consistent with the notion that sleep spindles are a marker for sleep stability, we found Ptchd1-knockout mice to display highly fragmented sleep.

Altogether, these findings provide direct evidence for reduced thalamic inhibition in Ptchd1-knockout mice and are consistent with impaired TRN output with ensuing deficits in sensory-related thalamic inhibition.

We have previously observed that thalamic inhibition is used to suppress unwanted sensory inputs during attention. The observed reduction in thalamic inhibition would predict that unwanted sensory inputs may become particularly distracting for Ptchd1-knockout mice.

Distractibility is often accompanied by hyperactivity in several human neurodevelopmental disorders such as ADHD. Classical ADHD-related hyperactivity is predicted to be treated effectively with amphetamines, as has been previously described in other mouse models of neurodevelopmental disease.

This study is the first to show that a TRN circuit deficit is central to a specific set of behavioural impairments in a human neurodevelopmental disease model. Using conditional knockout of Ptchd1, a gene with expression restricted to the TRN during early post-natal development, we mapped behavioural phenotypes onto their circuit substrates. We additionally discovered that modulation of SK channel function could be explored as a potential novel treatment strategy for PTCHD1 deletion patients with attention deficits and hyperactivity. Hyperactivity of TRN origin may be the motor equivalent of sensory distractibility, which could involve dysfunctional motor TRN-thalamic circuits. Future experiments exploring inhibitory control of motor thalamus will formally test this conjecture.

Although basic studies have shown the TRN to be central for attention and sleep spindles, our study directly shows how disease-relevant impaired TRN output can result in attention deficits, hyperactivity, and sleep disruption. This direct demonstration was made possible by developing SuperClomeleon photometry, a technique that can now be widely applied to disease models as a screen for impaired thalamic inhibition. It is possible that a ‘leaky thalamus’ caused by impaired TRN function underlies attention deficits, hyperactivity, and sleep disruption across various neurodevelopmental disorders,


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