Autism: New Medication Controls Hyperactive Neurons And Improves Symptoms

Researchers have discovered that a brain region called the reticular nucleus of the thalamus may play a central role in autism symptoms. In tests on mice exhibiting behaviors similar to those of the disorder, scientists observed that neurons in this region were hyperactive. When this excessive activity was controlled with medication and genetic techniques, the animals showed improvements in sleep, sensitivity to stimuli, and repetitive behaviors. These results suggest that this area of ​​the brain may be an important target for future autism treatments.

Autism Spectrum Disorders are brain developmental conditions that affect how a person perceives the world, relates to others, and organizes their behaviors. People with this diagnosis often have difficulties with communication and social interaction, a tendency toward repetitive behaviors, and may also have other associated problems, such as anxiety, hyperactivity, epilepsy, and sleep disturbances.

Recent research has shown that many of these characteristics may be related to the functioning of specific brain circuits, particularly the network connecting the thalamus and the cortex. This network is crucial because it regulates sleep, how we process sensory stimuli, attention, and even susceptibility to epileptic seizures.

Changes in this system have been observed in children and adults with autism, raising the hypothesis that it is central to understanding the condition.

The reticular nucleus of the thalamus, in particular, has sparked the interest of scientists. This nucleus acts as a sort of "gatekeeper" for sensory information, deciding which stimuli pass to the rest of the brain and which are blocked. It also plays a role in controlling sleep, fear, attention, and preventing seizures.

Neurons in this nucleus can fire in two ways: in rapid bursts, which produce strong inhibitory effects, or in more regular bursts. This balance is essential for maintaining the brain's normal electrical rhythms, such as sleep spindles or perceptual oscillations.

When this balance is lost, disorders such as schizophrenia, depression, attention deficit disorder, and possibly autism can develop.

To investigate this mechanism in more detail, the researchers used a model of genetically modified mice that lack the Cntnap2 protein. This protein has previously been linked to autism in humans, and mice lacking it exhibit behaviors similar to those of the disorder: hyperactivity, epileptic seizures, sleep disturbances, increased sensitivity to sensory stimuli, and difficulties with learning tasks.

Previous analyses showed that these animals had altered communication between neurons in different brain regions, but the specific role of the reticular nucleus of the thalamus remained unclear.

In the new study, scientists performed detailed recordings of the electrical activity of neurons in this nucleus and found that mice lacking the protein exhibited hyperexcitability. This means their neurons fired excessively, with increased internal oscillations and more episodes of rapid bursts than normal.

To confirm whether this abnormal activity was directly linked to autism-like symptoms, the researchers used two strategies to reduce the excitability of the reticular nucleus: a drug called Z944, which blocks calcium channels responsible for triggering these bursts, and a genetic engineering technique called chemogenetics, which allows certain neurons to be selectively "turned off" using control molecules.

The results were clear: when the hyperactivity of the reticular nucleus was reduced, the mice showed significant improvements in their behavior, including fewer repetitive actions, reduced hyperactivity, and less vulnerability to seizures.

These findings not only demonstrate that hyperexcitability of the reticular nucleus is one of the causes of autism-like behaviors in these animals, but also suggest that this brain region may be a promising target for future treatments.

Future research should aim to elucidate how circuit dynamics mediated by the thalamic reticular nucleus throughout the brain influence the broader neurobehavioral landscape of autism spectrum disorder, paving the way for precision, circuit-specific interventions.

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Reticular thalamic hyperexcitability drives autism spectrum disorder behaviors in the Cntnap2 model of autism

SUNG-SOO JANG, FUGA TAKAHASHI, and JOHN R. HUGUENARD

SCIENCE ADVANCES, 20 Aug 2025, Vol 11, Issue 34

DOI: 10.1126/sciadv.adw4682

Abstract: 

Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Although thalamocortical circuit dysfunction has been implicated in these symptoms, its precise roles in ASD pathophysiology remain poorly understood. Here, we examine the specific contribution of the reticular thalamic nucleus (RT), a key modulator of thalamocortical activity, to ASD-related behavioral deficits using a Cntnap2 knockout mouse model. Cntnap2−/− mice displayed increased seizure susceptibility, locomotor activity, and repetitive behaviors. Electrophysiological recordings revealed enhanced intrathalamic oscillations and burst firing in RT neurons, accompanied by elevated T-type calcium currents. In vivo fiber photometry confirmed behavior-associated increases in RT population activity. Notably, pharmacological and chemogenetic suppression of RT excitability via Z944, a T-type calcium channel blocker, and via C21 activation of the inhibitory DREADD hM4Di significantly improved ASD-related behaviors. These findings identify RT hyperexcitability as a mechanistic driver of ASD and highlight RT as a potential therapeutic target.