Major psychiatric risk gene linked to myelin and brain communication
· Medical Xpressby Olivia Dimmer, Northwestern University
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A new Northwestern Medicine study suggests a major psychiatric risk gene remains important well into adulthood and may influence brain communication, according to a study published in the Proceedings of the National Academy of Sciences.
In the study, investigators led by Peter Penzes, Ph.D., the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences, identified an unexpected biological pathway linking a well-known psychiatric risk gene, ANK3, to neuron myelination, a finding that may point toward more targeted treatments for bipolar disorder and related conditions.
"These results suggest that ANK3-associated illness may not arise exclusively from abnormal prenatal brain development. Instead, ankyrin-G, the protein produced by ANK3, appears to be continuously required to maintain normal brain function," Penzes said. He was the study's senior and corresponding author.
ANK3 has long been associated with increased risk for bipolar disorder and schizophrenia through common genetic variants. More disruptive mutations in the gene have also been linked to autism spectrum disorder and intellectual disability. Yet scientists have struggled to understand precisely how alterations in the gene affect the brain, Penzes said.
An adult role for ANK3
To better understand the link, the investigators used two mouse models and focused on the mouse version of ANK3, called Ank3. In one, Ank3 was deleted during embryonic development. In the other, the gene was removed from forebrain neurons after birth. They found that deleting the gene after birth produced many of the same behavioral changes seen when the gene was removed during development, suggesting that Ank3's role extends beyond merely shaping the developing brain.
The investigators also discovered that neurons lacking ankyrin-G showed reduced activity. At first glance, that result appears counterintuitive because the animals displayed hyperactive behavior. But Penzes said psychiatric disorders cannot be reduced to a simple question of whether the brain is more or less active overall.
"Normal behavior depends on the precise coordination and balance of activity across many interconnected cell types and brain regions," Penzes said. He is also the director of the Center for Autism and Neurodevelopment and a professor of neuroscience and pharmacology.
A clue in myelin proteins
Next, the scientists performed a large-scale protein analysis of the mouse brains. Among thousands of proteins examined, one of the biggest changes was a sharp decline in myelin basic protein (MBP), a critical component of myelin, the insulating material that allows nerve signals to travel efficiently.
"This result was surprising because Ank3 had been removed from neurons, yet one of the strongest consequences involved a protein made primarily by a different cell type," Penzes said. "It therefore reveals a previously unrecognized connection between neurons and the glial cells that produce myelin."
The finding may also help explain why brain imaging studies have repeatedly identified white matter abnormalities in people with bipolar disorder and schizophrenia, he said.
Lithium points to a treatment path
The investigators then tested lithium, one of the most effective current treatments for bipolar disorder. Previous work had shown lithium could reverse some behavioral abnormalities in mice lacking Ank3. In the new study, lithium restored MBP levels that had been reduced by ankyrin-G deficiency.
"Our findings suggest that one component of lithium's beneficial action may involve restoring MBP and supporting myelin-related processes," Penzes said. "Understanding this pathway could eventually help us develop more selective treatments that preserve lithium's benefits while avoiding some of its unwanted effects."
Building on the findings, Penzes and his collaborators are now investigating how changes in neurons influence neighboring brain cells, whether reduced MBP alters myelin structure or function, and whether the same mechanism occurs in people carrying ANK3 risk variants.
"Most importantly, can we restore MBP or myelin function using more selective treatments, and would doing so improve neuronal activity and behavior?" Penzes said.
Ultimately, Penzes said he hopes the work will help bridge the gap between genetic discoveries and new therapies for psychiatric disorders.
"This work may provide a path from genetic discovery to a more precise understanding of disease and, potentially, to safer and more targeted treatments," Penzes said.
Publication details
Sehyoun Yoon et al, Ank3 loss in adult forebrain excitatory neurons disrupts behavior, neuronal activity, membrane proteome, and myelination, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2606900123
Journal information: Proceedings of the National Academy of Sciences
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