Autism-related behaviors and susceptibility to seizures both arise from hyperactivity in a key region of a sensory-information-processing circuit in the brain, a new study finds. The results may help explain the frequent co-occurrence of autism and epilepsy and point to a new therapeutic target.
According to current estimates, about 12 percent of people with autism experience seizures, exceeding the less than 1 percent of people with epilepsy in the general population. Researchers have long attributed the overlap between autism and epilepsy to an imbalance of excitation and inhibition in the brain, says Joseph Gleeson, professor of neuroscience at the University of California, San Diego, who did not contribute to the new work.
But this study really “drills down” into a specific brain circuit and cell type that may be involved in both autism and epilepsy, Gleeson adds. “There’s an incredible level of mechanistic insight in the paper.”
The work focuses on the thalamocortical circuit, which is involved in sensory processing, cognition and other important functions. Dysfunction in this pathway may be implicated in both autism and epilepsy, prior studies suggest.
The investigators on the new study examined the CNTNAP2–knockout mouse model of autism, which, in addition to exhibiting autism-related behaviors—such as hyperactivity, disrupted sleep and impaired sensory processing—is also prone to seizures. They zoomed in on electrical activity within a small region called the reticular thalamic nucleus. This thin, shell-like structure sends inhibitory signals to the thalamus, which ultimately makes the reticular thalamic nucleus a gatekeeper for processes that depend on the thalamocortical circuit.
The findings were published 20 August in Science Advances.
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eticular thalamic nucleus cells of CNTNAP2 mice show heightened excitability—with an increase in high-frequency action potentials compared with wildtype animals, the investigators found. This was linked to an increase in neural rhythms within the thalamocortical circuit, which arises because of a unique feature of certain thalamic cells, called “post-inhibitory rebound firing,” in which inhibition can paradoxically lead to an increase in activity. These effects were driven by an increase in the function of a specific type of ion channel called T-type calcium channels, the team further observed.
Injecting the CNTNAP2 mice with Z944, a drug that selectively blocks T-type calcium channels and has previously shown anti-epilepsy effects in animals, suppressed seizures and reversed autism-like behaviors, such as repetitive movements and impairments in social behavior.
Inhibiting activity in the reticular thalamic nucleus using chemogenetics produced similar effects. On the other hand, using chemogenetics to enhance activity in this brain structure introduced autism-like behaviors in wildtype mice.
These results suggest that, at least in a subset of autistic people who carry variants in the CNTNAP2 gene, certain drugs used to treat epilepsy may ease autism-related behaviors, says study investigator John Huguenard, professor of neurology and neurological sciences at Stanford University.
The mice in the study do not perfectly model autism, though, and work with other autism models is needed before drawing firm conclusions, Huguenard adds. “I think this is super exciting, but it’s the kind of thing you want to see some replication [of] in other studies before you push ahead for clinical application.”
The findings jibe with independent evidence that the same thalamocortical circuit malfunctions in other autism models, although in different ways, says Zhanyan Fu, associate director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, who was not involved in the new research. For example, reticular thalamic nucleus neurons are hypoactive, rather than hyperactive, in autism model mice missing part of the PTCHD1 gene, a 2016 study found. “I was very excited to see this [new study],” Fu says.
Putting the studies together, the work points to the importance of balance in the activity of the reticular thalamic nucleus, which serves as a “gateway of information flow” within the thalamocortical circuit, according to Fu. But the fact that the new findings suggest different pathophysiological mechanisms underlying autism-related behaviors than past work within the same pathway reinforces the notion that autism is not a single entity and instead involves multiple subgroups, Fu says.