Their study, published in Science Advances, shows that excessive activity in a brain region known as the reticular thalamic nucleus (RT) may drive autism-like behaviors in mice.
“Although thalamocortical circuit dysfunction has been implicated, its precise roles in ASD pathophysiology remain poorly understood,” the authors stated.
Autism spectrum disorders are marked by social difficulties, repetitive behaviors, and sensory sensitivities. Importantly, around 30% of autistic individuals also develop epilepsy, compared with just 1% of the general population. This overlap has long suggested that both conditions may share underlying brain mechanisms.
The RT, located within the thalamocortical (TC) circuits that regulate sensory information and sleep, acts as a filter. When this inhibitory layer becomes hyperactive, it disrupts normal brain rhythms and can trigger seizures, sensory overload, and behavioral changes.
Using Cntnap2 knockout mice, a well-established autism model, the Stanford team observed classic autism-like traits: hyperactivity, repetitive grooming, reduced social interaction, and seizures. Brain recordings showed that RT neurons fired abnormally, with stronger T-type calcium currents and disrupted oscillations across connected circuits.
In live mice, fiber photometry confirmed that RT activity spiked not only during sensory stimulation and social encounters, but also spontaneously at rest. This consistent overactivity pointed to a causal role in the observed behavioral deficits.
Experimental drug reverses symptoms
To test whether suppressing this overactivity could improve behavior, the researchers applied two approaches. First, they administered Z944, an experimental epilepsy drug that blocks T-type calcium channels. In the autism-model mice, the treatment reduced RT hyperactivity, restored normal social interactions, and diminished repetitive grooming.
Second, they employed chemogenetics, a technique where neurons are engineered to respond to synthetic drugs. By silencing RT neurons, they improved the behavior of knockout mice. Conversely, artificially increasing RT activity in healthy mice was enough to trigger autism-like symptoms.
“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 explained.
These findings provide a mechanistic explanation for why autism and epilepsy often co-occur, as both involve abnormal thalamic circuit activity. They also suggest that drugs already in development for epilepsy might be repurposed for autism therapies.
“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,” the researchers noted.
Still, the authors cautioned that further work is required. Researchers must find out when RT overactivity begins during development and if early treatment can help. They also stressed the importance of testing these approaches in different autism models and, eventually, in human trials.
“Future research should aim to elucidate how RT-mediated circuit dynamics throughout the brain influence the broader neurobehavioral landscape of ASD,” they concluded.
Earlier, it was reported that Chinese scientists had achieved a breakthrough in neuroscience by successfully transforming human stem cells into dopamine-producing brain cells and transplanting them into mice, which led to a marked reduction in depressive behaviors.