Experimental Epilepsy Drug Z944 Reverses Autism-Like Behaviors in Preclinical Study
Key Insights
Stanford Medicine researchers discovered that hyperactivity in the reticular thalamic nucleus (search) drives autism-like behaviors in mice and can be reversed with the experimental epilepsy (search) drug Z944.
The study found that Z944 treatment reduced hyperactivity, restored normal social preference, and decreased repetitive grooming behaviors in Cntnap2 knockout mice.
The findings provide mechanistic insight into why autism and epilepsy (search) frequently co-occur, with approximately 30% of autistic individuals developing epilepsy compared to 1% of the general population.
Stanford Medicine researchers have identified a potential new therapeutic approach for autism spectrum disorders (search) (ASDs) using an experimental epilepsy (search) drug that targets overactive brain circuits. The study, published in Science Advances, demonstrates that the drug Z944 can reverse autism-like behaviors in mice by suppressing hyperactivity in a specific brain region.
Targeting Thalamocortical Circuit Dysfunction
The research focused on the reticular thalamic nucleus (search) (RT), a key inhibitory layer within thalamocortical circuits (search) that filters sensory signals and helps regulate sleep and seizures. Using Cntnap2 knockout mice, a widely used autism model, the team found that RT neurons were unusually excitable, firing in bursts more frequently than in healthy mice and showing stronger T-type calcium currents.
"Although thalamocortical circuit dysfunction has been implicated, its precise roles in ASD pathophysiology remain poorly understood," the authors noted. The study revealed that RT activity spiked during sensory stimulation and social encounters, often becoming overactive even at rest.
Dual Approach Validates Therapeutic Target
The researchers tested two methods to reduce RT hyperactivity. First, they administered Z944, an experimental drug that blocks T-type calcium channels (search) currently under investigation for epilepsy (search) treatment. In the knockout mice, Z944 reduced hyperactivity, restored normal social preference, and decreased repetitive grooming behaviors.
The team also employed chemogenetics, engineering RT neurons to respond to designer drugs that could modulate their activity on demand. Silencing these neurons improved behavior in knockout mice, while artificially increasing RT activity in normal mice was sufficient to produce autism-like traits.
"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 stated.
Mechanistic Link Between Autism and Epilepsy
The findings help explain the strong association between autism and epilepsy (search), with approximately 30% of autistic individuals developing epilepsy compared to only 1% of the general population. By demonstrating that both conditions involve abnormal activity in the same thalamic circuits, the study provides a mechanistic explanation for their frequent co-occurrence.
The research showed that overactivity in the RT region drives social deficits, repetitive actions, and hyperactivity, offering insight into how ASD symptoms arise at the circuit level.
Clinical Translation Potential
Since Z944 is already under investigation for epilepsy (search) treatment, the drug may have potential for repurposing in autism therapy. However, the authors noted that whether these approaches would benefit autistic individuals without epilepsy or intellectual disabilities remains to be determined.
"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 concluded.
Future Research Directions
The study authors emphasized the need for longitudinal studies to determine when RT hyperactivity emerges during development and whether early intervention could make a difference. Testing RT-targeting approaches across different autism models and eventually in humans will be essential for clinical translation.
"Future research should aim to elucidate how RT-mediated circuit dynamics throughout the brain influence the broader neurobehavioral landscape of ASD," the authors added.
The research represents a significant step toward understanding the neural mechanisms underlying autism spectrum disorders (search) and identifying potential therapeutic targets for intervention.