Summary: Researchers have uncovered a link between the immune gene regulator STAT1 and hyperactive behaviors in mice, offering new insights into neurodevelopmental disorders like autism and ADHD. STAT1, vital for infection response, also influences brain cell activity, particularly dopamine neurons involved in motivation and learning.
In mice with prolonged STAT1 signaling, hyperactivity and reduced neural activity in key brain regions were observed. The study opens the door to targeting STAT1 for potential therapies to address neurobehavioral disorders.
Key Facts:
- Prolonged STAT1 signaling in dopamine neurons led to hyperactivity and fewer neurons in regions tied to learning and reward.
- The study highlights communication between the immune system and brain development.
- Future research will explore therapies targeting STAT1 to treat neurodevelopmental disorders.
Source: Duke University
Building on research that has linked immune responses with certain neurobehavioral conditions, researchers at Duke Health have identified how a key infection-fighting function is involved in triggering hyperactive behaviors in mice.
The finding, appearing this month in the journal Brain, Behavior, and Immunity, adds insight to an on-off switch for genes called STAT1. This gene regulator plays a pivotal role in the immune system’s response to infections and has also been implicated in various neurodevelopmental disorders such as autism and ADHD.
“A lot of these pathways that have been discovered in the immune system also play important roles in the brain,” said senior author Anthony Filiano, Ph.D., assistant professor in the departments of Neurosurgery and Pathology at Duke University School of Medicine and a faculty member in the Marcus Center for Cellular Cures.
“There is a very robust communication between the two systems. This is intriguing because the immune system is very targetable from a therapy perspective.”
Filiano and colleagues at Duke worked with a team at Columbia University that bred mice with a STAT1 mutation. Using these mice, they were able to over-activate the immune pathway in different cell types of the brain, including dopamine neurons, which help modulate reward, motivation, and motor control.
“Prolonged STAT1 signaling in neurons, beginning during embryonic development, led to hyperactive behavior and fewer neurons and reduced neural activity in an area of the brain involved in learning, memory, reward and motivation,” Filiano said.
“These results suggest that STAT1 signaling in dopamine neurons has a role in regulating behavior and disruption of this signaling may contribute to neurodevelopmental disorders.”
Filiano said further studies will explore whether it’s possible to target the STAT1 pathway with therapies: “We need to understand its function and target it more specifically before we move forward,” he said.
In addition to Filiano, study authors include Danielle N. Clark, Shelby Brown, Li Xu, Rae-Ling Lee, Joey V. Ragusa, Zhenghao Xu, and Joshua D. Milner.
Funding: The study received funding support from the National Institutes of Health (NS123084), the Marcus Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) intramural research program.
About this genetics, ADHD, and Autism research news
Author: Sarah Avery
Source: Duke University
Contact: Sarah Avery – Duke University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Prolonged STAT1 signaling in neurons causes hyperactive behavior” by Anthony Filiano et al. Brain, Behavior, and Immunity
Abstract
Prolonged STAT1 signaling in neurons causes hyperactive behavior
The interferon (IFN)-induced STAT1 signaling pathway is a canonical immune pathway that has also been implicated in regulating neuronal activity.
The pathway is enriched in brains of individuals with autism spectrum disorder (ASD) and schizophrenia (SZ). Over-activation of the STAT1 pathway causes pathological transcriptional responses, however it is unclear how these responses might translate into behavioral phenotypes.
We hypothesized that prolonged STAT1 signaling in neurons would be sufficient to cause behavioral deficits associated with neurodevelopmental disorders.
In this study, we developed a novel mouse model with the clinical STAT1 gain-of-function mutation, T385M, in neurons. These mice were hyperactive and displayed neural hypoactivity with less neuron counts in the caudate putamen.
Driving the STAT1 gain-of-function mutation exclusively in dopaminergic neurons, which project to the caudate putamen of the dorsal striatum, mimicked some hyperactive behaviors without a reduction of neurons.
Moreover, we demonstrated that this phenotype is neuron specific, as mice with prolonged STAT1 signaling in all excitatory or inhibitory neurons or in microglia were not hyperactive.
Overall, these findings suggest that STAT1 signaling in neurons is a crucial player in regulating striatal neuron activity and aspects of motor behavior.
