Some cases of schizophrenia may be caused by malformations in the skull, new research suggests.
The study, published Dec. 5 in the journal Nature Communications, focuses on 22q11.2 deletion syndrome, a chromosomal disorder in which one copy of chromosome 22 is missing a small chunk. (Humans typically carry 23 pairs of chromosomes, including one copy of chromosome 22 from each parent.)
The syndrome — which affects roughly 1 in 2,150 live births — can affect many different parts of the body, potentially causing heart abnormalities, immune problems, cleft palate and developmental delays. People with the syndrome also have a 25% to 30% chance of developing schizophrenia in adolescence or early adulthood, studies suggest. Among other symptoms, schizophrenia can cause psychosis, or breaks with reality such as hallucinations, and it can also disrupt people's ability to maintain social relationships and express emotions.
The study suggests this risk of schizophrenia may stem from malformations in the skull that restrict the growth of part of the brain. And these malformations can be traced back to a gene called Tbx1.
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"What is interesting about Tbx1 is that it is not very well expressed in the brain, especially adolescent or adult brain," study co-author Dr. Stanislav Zakharenko, director of the Division of Neural Circuits and Behavior in St. Jude's Department of Developmental Neurobiology, said in a statement. That means that the brain does not "switch on" Tbx1 much.
"Rather, it's expressed in the surrounding tissues, namely bone, cartilage and vasculature tissues," Zakharenko said. "It is very unlikely that Tbx1 directly affects the brain at all."
To pinpoint Tbx1, Zakharenko and colleagues studied lab mice with the 22q11.2 deletion and mice without it. In the former mice, they saw differences in the cerebellum — part of the brain involved in coordinating movements, maintaining posture and learning new skills, among other cognitive functions. Two of the cerebellum's lobes were about 70% smaller in the mice with the deletion.
This size loss made it more difficult for mice to complete tasks that required them to learn movements, experiments suggested. This difficulty stemmed from issues with modulating the vestibulo-ocular reflex (VOR), a reflex that helps stabilize the visual field during head movements. For humans, a lack of visual stabilization can make people's faces difficult to recognize, and issues with both the VOR and facial recognition are common in schizophrenia.
Despite these observations in mice, the researchers didn't see anything particularly unusual about the cellular makeup of the too-small lobes or how their cells formed. What they did see was that the skull bone that houses that part of the brain was malformed.
There should have been a cozy "pocket" for that part of the cerebellum to grow into, but the pocket was much shallower than usual and thus crowded the tissue. It turned out that the gene Tbx1 was the issue because, without the gene, bone cells don't mature as they normally would, the team found.
To see if people with 22q11.2 deletion syndrome have similar brain abnormalities, the team looked at magnetic resonance imaging (MRI) scans from 80 people with the condition and from 68 without. Like the mice, people with the syndrome showed a distinct size decrease in those same lobes of the cerebellum.
However, this size loss was "less profound" in humans than in the mice, the researchers wrote in their paper. They don't yet know exactly why that might be.
This line of research is still in its early days — but the current data points to a potential "previously unrecognized" link between 22q11.2 deletion syndrome and schizophrenia.
Looking forward, the researchers plan to further investigate how this mechanism might set the stage for psychosis down the line, through its indirect impact on other parts of the brain that plug into the cerebellum.
