Hyperactivity in reticular thalamic nucleus drives autism-like behaviors in mice

Stanford Medicine scientists investigating the neurological underpinnings of autism spectrum disorder have found that hyperactivity in a specific brain region could drive behaviors commonly associated with the disorder.

Using a mouse model of the disease, the researchers identified the reticular thalamic nucleus - which serves as a gatekeeper of sensory information between the thalamus and cortex - as a potential target for treatments.

Moreover, they were able to reverse symptoms similar to those of autism - including susceptibility to seizures, heightened sensitivity to stimulus, increased motor activity, repetitive behaviors and decreased social interactions - by giving the mice drugs that suppressed this area of the brain.

The same drugs are being studied for the treatment of epilepsy, highlighting where the processes underlying autism spectrum disorders and epilepsy may overlap in the brain and why they often occur in the same patients.

The findings will be published Aug. 20 in Science Advances. The senior author of the study is John Huguenard, PhD, professor of neurology and neurological sciences. The lead author is Sung-Soo Jang, PhD, a postdoctoral scholar in neurology and neurological sciences.

The neural circuitry connecting the thalamus and cortex has been implicated in autism in both humans and animal models, but the role of the reticular thalamic nucleus was not clear.

In the new study, the researchers recorded the neural activity of this brain region in mice while observing the animals' behavior. In mice that had been genetically modified to model autism (Cntnap2 knockout mice), the reticular thalamic nucleus showed elevated activity when the animals encountered stimuli like light or an air puff as well as during social interactions. The brain region also showed bursts of spontaneous activity, causing seizures.

Epilepsy is much more prevalent in people with autism than in the general population - 30% versus 1% - though the mechanisms are not well understood. Recognizing this connection, the researchers tested an experimental seizure drug, Z944, and found that it reversed behavioral deficits in the autism mouse model.

With a different experimental treatment that genetically modifies neurons to respond to designer drugs, known as DREADD-based neuromodulation, the researchers could suppress overactivity in the reticular thalamic nucleus and reverse behavioral deficits in the autism mouse model. They could even induce these behavioral deficits in normal mice by ramping up activity in the reticular thalamic nucleus.

The new findings highlight the reticular thalamic nucleus as a novel target for the treatment of autism spectrum disorders.