(© Feng Yu - stock.adobe.com)

Stanford Scientists Find Brain Region That May Control Symptoms In A Nutshell

Stanford researchers found that overactive neurons in the reticular thalamic nucleus drive autism-like behaviors in mice.

Calming these neurons with Z944 (a calcium channel blocker) or DREADD genetic tools restored normal behavior.

Treated mice showed improved social interaction, reduced repetitive grooming, and normalized activity.

While promising, these results are from mouse studies only; human trials are needed before any treatment applications.

STANFORD, Calif. — Scientists at Stanford University have identified a specific brain region that appears to drive core autism symptoms in mice and successfully improved those behaviors using targeted treatments. The breakthrough focuses on overactive neurons deep in the brain that serve as gatekeepers for sensory information, controlling what signals reach conscious awareness.

The findings, published in Science Advances, come from mouse studies, a standard model in autism research, and more work is needed before testing in humans. Still, the results point toward potential therapies that may address autism’s biological foundations rather than just managing symptoms.

Overactive Brain Cells Disrupt Normal Function

The problem originates in a brain structure called the reticular thalamic nucleus, which acts like a traffic control system for sensory information. In healthy brains, this region determines which sensory signals (sounds, sights, and touches) warrant attention from higher brain areas. In autism-model mice, however, these neurons fired in rapid, excessive bursts that scrambled normal brain communication.

Stanford researchers studied mice engineered to lack Cntnap2, a gene strongly linked to autism in humans. These mice exhibited classic autism-like traits, including social avoidance of other mice, repetitive grooming, hyperactivity, and increased seizure susceptibility. Brain examinations revealed that reticular thalamic nucleus neurons were firing far more frequently than normal.

Scientists traced this hyperactivity to overactive calcium channels, proteins that regulate how neurons communicate. In autism-model mice, these T-type calcium channels enabled neurons to burst-fire much more easily, resulting in disrupted brain signals that manifested as behavioral symptoms.

Mice given Z944, an experimental seizure drug, showed major behavioral improvements when it came to autism-like traits. (© filin174 – stock.adobe.com) Two Treatment Methods Show Promise

Researchers tested whether reducing this neural overactivity could restore normal behavior using two different approaches, both of which produced remarkable results.

First, they administered Z944, a drug that blocks the problematic calcium channels, to the mice. Mice receiving this treatment showed substantial behavioral improvements, including decreased hyperactivity, restored social preferences, and cessation of excessive grooming behaviors. Z944 has already undergone human testing for treating certain seizure types, which could speed its potential path to autism trials.

The second method used advanced genetic tools called DREADDs (designer receptors exclusively activated by designer drugs). Scientists modified the mice so specific neurons could be controlled using engineered proteins and matching drugs. When they used this technique to quiet reticular thalamic nucleus activity, autism-like behaviors improved substantially again.

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Most convincingly, researchers demonstrated the reverse: artificially increasing activity in these brain cells caused normal mice to develop autism-like behaviors, including reduced social interaction and increased repetitive actions.

Targeting the Root Instead of Symptoms

Previous autism research concentrated mainly on the brain’s outer layer, where complex thinking occurs. But this study reveals that autism’s behavioral symptoms may actually start in a much deeper, more primitive brain region that handles basic sensory processing and attention.

The reticular thalamic nucleus connects to many brain areas involved in sensory processing, attention, and emotional regulation. When it becomes overactive, the resulting disruption affects multiple brain networks simultaneously, which explains why autism involves such varied symptoms affecting social behavior, sensory processing, and repetitive actions.

Most neurons in this brain region produce a protein called parvalbumin, which previous research has repeatedly connected to autism. Earlier studies found fewer parvalbumin-producing neurons in autism models and in brain tissue from people with autism.

Current autism treatments focus on behavioral interventions and medications that address secondary symptoms like anxiety or hyperactivity. A treatment targeting T-type calcium channels could potentially address autism’s core features directly by correcting the underlying brain dysfunction rather than managing its effects.

Moving from laboratory discovery to human treatment requires additional studies in other autism models and eventual human clinical trials. Since Z944 has already been tested in humans for other conditions, this could potentially accelerate development of autism-specific treatments based on these principles.

If these results eventually apply to humans, individuals with autism and their families could one day access more effective treatments that address the condition’s neurobiological foundation rather than just managing symptoms.

Disclaimer: This study was conducted in mice and does not represent an approved treatment for autism in humans. Findings are preliminary and require further research, including human clinical trials, before any medical application. Individuals should not interpret this research as medical advice or alter existing treatments without consulting qualified healthcare professionals.

Paper Summary Methodology

Researchers used Cntnap2 knockout mice, which lack a gene strongly associated with autism in humans and display autism-like behaviors including hyperactivity, reduced social interaction, and repetitive behaviors. The team employed multiple experimental approaches: whole-cell patch-clamp recordings to measure electrical activity in individual brain cells, fiber photometry to track neural activity in living mice during behaviors, optogenetics to stimulate specific neurons with light, and chemogenetics (DREADDs) to selectively activate or inhibit neurons. They conducted behavioral tests including open field tests for hyperactivity, three-chamber tests for social preference, grooming assessments, and seizure susceptibility measurements using electroencephalogram recordings.

Results

The study found that neurons in the reticular thalamic nucleus of autism-model mice showed increased burst firing and elevated T-type calcium currents compared to normal mice. In vivo recordings revealed heightened neural activity during various behaviors including light exposure, social interactions, and seizure induction. Both pharmacological treatment with Z944 (a T-type calcium channel blocker) and chemogenetic suppression of reticular thalamic nucleus activity significantly improved autism-like behaviors including hyperactivity, social deficits, and repetitive grooming. Conversely, artificially activating these neurons in normal mice induced autism-like behaviors, demonstrating a causal relationship.

Limitations

The study used only male mice since female Cntnap2 knockout mice don’t show significant behavioral abnormalities. The research focused on a single genetic model of autism, and findings may not generalize to other forms of the condition. Voltage-clamp recordings of T-type calcium currents represent a technical compromise due to the difficulty of completely isolating these currents in brain slice preparations. The study didn’t examine different subpopulations of reticular thalamic nucleus neurons or assess long-term developmental effects of the interventions.

Funding and Disclosures

This research was supported by SFARI award number 633450 and NIMH grant R01 MH121075. The authors declared no competing interests. All animal procedures were approved by the Stanford Administrative Panel on Laboratory Animal Care and conducted according to National Institutes of Health guidelines.

Publication Information

The study “Reticular thalamic hyperexcitability drives autism spectrum disorder behaviors in the Cntnap2 model of autism” was conducted by Sung-Soo Jang, Fuga Takahashi, and John R. Huguenard from the Department of Neurology and Neurological Sciences at Stanford University School of Medicine. It was published in Science Advances, volume 11, article number eadw4682, on August 20, 2025.