4 Minutes
Stanford Medicine researchers report that excessive activity in the reticular thalamic nucleus (RTN) can drive behaviors associated with autism spectrum disorder in a mouse model. By using experimental pharmacology and engineered neuromodulation, the team suppressed hyperactivity in this sensory-filtering brain region and reversed multiple autism-like signs in mice, including seizures, sensory over-reactivity, repetitive behavior, hyperactivity, and reduced social interactions. Credit: Shutterstock
Scientific background
The thalamus and cortex form a central sensory relay that shapes how the brain interprets external cues. The RTN is a small inhibitory nucleus that gates signals between the thalamus and cortex, regulating attention and sensory filtering. Prior clinical and animal studies have linked thalamocortical circuitry to autism, but the specific role of the RTN remained unclear. Using a genetic mouse model that lacks the Cntnap2 gene, researchers probed neural dynamics in the RTN while monitoring behavior to identify how local changes in activity map onto autism-like phenotypes.
Experiment details and methods
Recording and behavioral correlation
The team recorded RTN neuronal firing in freely behaving mice and correlated activity patterns with reactions to visual and tactile stimuli and with social interactions. In Cntnap2 knockout mice, RTN neurons showed abnormally high baseline and stimulus-evoked firing, and spontaneous bursts that sometimes precipitated seizures.
Interventions: drug and DREADD neuromodulation
To test causality, researchers applied two complementary interventions. First, they administered an experimental seizure drug, Z944, which reduces RTN excitability; treatment normalized neural firing and rescued behavioral deficits. Second, they used DREADD-based chemogenetic neuromodulation to selectively suppress or activate RTN neurons. Suppressing RTN hyperactivity reversed autism-like behaviors in the model, while artificially increasing RTN firing in healthy mice produced similar behavioral changes, demonstrating bidirectional control.
Key discoveries and implications
The study, published in Science Advances and led by senior author John Huguenard and lead author Sung-Soo Jang, indicates that RTN hyperactivity can be sufficient to produce a cluster of autism-relevant symptoms in mice. The findings also highlight overlapping mechanisms between autism and epilepsy: seizure susceptibility is far higher among people with autism than in the general population, and Z944 and related compounds are being explored for epilepsy treatment. Targeting RTN circuits may therefore offer a dual opportunity to reduce both seizures and core behavioral symptoms in some individuals.
Related technologies and future prospects
This work illustrates how targeted neuromodulation, whether pharmacological or receptor-based (DREADD), can probe and reverse circuit dysfunction. Translating these results to humans will require safety testing, identification of patient subgroups with RTN-linked pathophysiology, and development of clinically viable modulators or neuromodulation approaches, such as focused brain stimulation or selective pharmacology.
Expert Insight
Dr. Maria Alvarez, a neuroscientist specializing in circuit disorders, comments: "This study is an important proof of principle. It narrows a complex problem—the behavioral diversity of autism—down to a manipulable circuit node. While mice are not humans, the RTN's role in sensory gating makes it a compelling therapeutic target for further translational research."
Conclusion
The Stanford study identifies the reticular thalamic nucleus as a novel circuit locus whose hyperactivity produces autism-like behaviors in mice. By reversing that hyperactivity with an experimental antiseizure drug and with chemogenetic neuromodulation, researchers reversed multiple behavioral deficits, underscoring a shared neurobiological link between autism and epilepsy and pointing to new directions for targeted therapies.
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