Tracing the effects of a specific gene deletion in mice revealed how it disrupts a brain circuit that filters out superfluous sensory input, such as background noise, so that the brain can focus on important information. The findings suggest that defects in this circuit could underlie attention-related symptoms across different human behavioral disorders, and how treatment might be designed to correct it.
About 1 percent of people with autism spectrum disorders (ASD) and intellectual disability have a mutation in the gene PTCHD1 (patched-domain containing protein 1). People with an altered PTCHD1 gene have symptoms that include attention deficit, hyperactivity, sleep abnormality, low muscle tone, and learning disability.
The PTCHD1 gene is expressed or active in the thalamus, a part of the brain that plays roles in sensory processing, motor control, and sleep. Investigators at New York University’s Langone Medical Center and the Massachusetts Institute of Technology, led by Langone’s Michael Halassa, M.D., Ph.D., found that, early in development, the gene is selectively expressed in a part of the thalamus called the thalamic reticular nucleus (TRN). The TRN comprises a set of inhibitory neurons that regulate the relay of sensory information from the thalamus to the cortex, where higher cognitive functions, thought, and decision-making are centered.
To determine how changes in the PTCHD1 gene alter TRN function and attention, the team selectively deleted (or knocked out) the PTCHD1 gene only in the TRN (global deletion of PTCHD1 results in broader and more severe deficits than targeted deletion). The mice without the gene showed attention deficit, hyperactivity, and disrupted sleep, suggesting an origin for those effects in the TRN. The attention deficit was not a general failure in attention, but an inability to filter out distraction; the mice had difficulty with tests that challenged their ability to carry out a task (responding to a light flash to get a reward) while being distracted.
To determine, down to the molecular level, how the gene loss altered TRN function, the investigators looked at the patterns of electrical activity in these neurons. They were able to pinpoint a change in activity of channels that shuttle potassium (SK channels) across the cell membrane; the exchange of ions across the membrane determines the conditions that make it more or less likely that a neuron will “fire” electrically. They then confirmed the connection between the SK channels and TRN activity using an approach they developed to monitor real-time changes in the inhibitory activity of TRN neurons. The system uses a fluorescent protein to track movements of chloride ions, an indicator of electrical signaling activity in the neuron. Binding of choride to the protein produces optical signals and a means of tracking the electrical activity of TRN neurons with great precision. In mice with the deleted gene (but not mice with the gene unaltered) the TRN inhibitory activity in response to light pulses was reduced.
Pinpointing the SK channels as the gene-related origin of the change in TRN activity suggested a target for restoring function. The team treated mice missing PTCHD1 with a compound that boosts SK channels; the treatment corrected the attention deficits and hyperactivity. Aiming medication development towards restoring SK channel function may lead to future means to treat attention symptoms that originate with the brain circuit identified in this research.
While this work provides clues to the known effects of PTCHD1 gene mutations in children with ASD and intellectual disability, the work also provides details on a brain circuit in which disruptions may underlie attention-related symptoms across different neurodevelopmental and psychiatric disorders. Difficulty selectively filtering out extraneous information has implications for focus and learning, as well as dealing with the daily barrage of sensory experience, something that is difficult for people with ASD.
“Our studies have given us a better understanding of how the brain’s processing of sensory information, a key impairment in autism and ADHD, can affect higher level cognitive functions, such as attention and decision making,” says study senior investigator Michael Halassa. In animals and people, “low-level disruption from an inability to focus can lead to higher level problems with memory, thinking, and long-term learning.”