A drug being studied for epilepsy treatment may also hold promise for autism spectrum disorders (ASDs).
In a new paper from Stanford Medicine, published in Science Advances, scientists found that overactivity in a specific region of the brain drives autism-like behaviors in mice. Treating the animals with the experimental drug Z944, or using neuromodulation to quiet this region, reversed their observed social and behavioral deficits.
Autism and epilepsy share brain circuit hyperactivity
ASDs are neurodevelopmental conditions characterized by social challenges and repetitive behavior. Alongside these core traits, many autistic people experience sensory sensitivities, disrupted sleep and seizures.
Autism and epilepsy are closely linked, with ~30% of autistic individuals also developing epilepsy, compared to only ~1% of the general population. This overlap suggests that shared brain mechanisms may be at play; however, the biological mechanisms connecting the two conditions is still unclear.
Research has increasingly focused on the thalamocortical (TC) circuits, which connect the thalamus, where sensory information first arrives, to the cortex, where it is processed. When these circuits are disrupted, sensory overload and abnormal sleep patterns can result. Imaging studies have found differences in the structure and function of the thalamus in people with ASDs.
Within this network, the reticular thalamic nucleus (RT) is a key inhibitory layer that filters sensory signals and helps regulate sleep and seizures. Some studies have hinted that dysfunction in this region may be relevant to autism.
“Although thalamocortical circuit dysfunction has been implicated, its precise roles in ASD pathophysiology remain poorly understood,” said the authors.
The new study set out to test whether hyperactivity in the RT contributes to autism-related behaviors – and whether suppressing this activity could reduce them.
Autism mouse model shows brain changes and drug response
The team worked with Cntnap2 knockout mice, a widely used model for ASD. The mice were more active than controls, groomed excessively, showed little interest in social interaction and were more prone to seizures – all traits that provide a reliable baseline of autism-like behaviors.
Using brain slice recordings, the researchers found that the RT was unusually excitable in the Cntnap2 mice. RT neurons fired in bursts more often than in healthy mice and showed stronger T-type calcium currents, the electrical signals that drive this firing. The wider thalamic circuits, which connect the RT to the cortex, also displayed abnormal oscillations.
In living mice, fiber photometry revealed that RT activity spiked during sensory stimulation and social encounters, and it often became overactive, even at rest.
The team then tested two ways to reduce this hyperactivity. First, they gave the mice Z944, an experimental drug that blocks T-type calcium channels and is already being studied for epilepsy. In the knockout mice, Z944 reduced hyperactivity, restored normal social preference and cut back on repetitive grooming.
In a second approach, they used chemogenetics. By engineering RT neurons to respond to a designer drug, they could turn their activity up or down on demand. Silencing the neurons improved behavior in knockout mice, while artificially ramping up RT activity in normal mice was enough to produce autism-like traits.
Chemogenetics
Chemogenetics is a technique that uses engineered receptors and synthetic drugs to control the activity of specific neurons with high precision.
Autism treatments may target brain circuits in future research
“Both Z944-mediated pharmacological inhibition and DREADD-based neuromodulation of RT neurons offer a powerful and targeted approach to ameliorate ASD-related behaviors,” the authors said.
By linking overactivity in this brain region to social deficits, repetitive actions and hyperactivity, the study offers a mechanistic explanation for how ASD symptoms arise. It also helps explain why epilepsy and ASD so often occur together, since both conditions involve abnormal activity in the same thalamic circuits.
Since drugs such as Z944 are already under investigation for epilepsy, there may be potential to repurpose them for autism treatment.
However, whether these approaches would also benefit autistic individuals who do not experience epilepsy or intellectual disabilities, is yet to be discovered.
“If this represents a common mechanism underlying ASD circuit pathology across diverse genetic backgrounds, then compounds such as Z944 may offer an effective therapeutic strategy,” said the authors.
Longitudinal studies are needed to show when RT hyperactivity emerges during development and whether early intervention makes a difference. Testing RT-targeting approaches across different autism models, and eventually in humans, will also be essential.
“Future research should aim to elucidate how RT-mediated circuit dynamics throughout the brain influence the broader neurobehavioral landscape of ASD,” the authors added.
Reference: Jang SS, Takahashi F, Huguenard JR. Reticular thalamic hyperexcitability drives autism spectrum disorder behaviors in the Cntnap2 model of autism. Sci Adv. 2025. doi: 10.1126/sciadv.adw4682
This article is a rework of a press release issued by Stanford Medicine. Material has been edited for length and content.