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A gene mutation may trap the brain in the wrong reality in schizophrenia patients

A schizophrenia-linked gene mutation may lock the brain into outdated beliefs—but scientists just found a way to flip the switch back.

Date:

April 3, 2026

Source:

Massachusetts Institute of Technology

Summary:

A newly identified gene mutation may help explain why schizophrenia patients struggle to update their understanding of reality. The mutation disrupts a brain circuit involved in flexible decision-making, causing mice to stick with outdated choices even when conditions change. Researchers pinpointed the issue to a key thalamus–prefrontal cortex pathway. By reactivating this circuit, they were able to restore normal behavior—raising hope for future therapies.

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FULL STORY

A gene mutation linked to schizophrenia may impair the brain’s ability to adapt to new information, leading to rigid, outdated thinking. Credit: Shutterstock

A common feature of schizophrenia is difficulty using new information to understand the world. This challenge can make decision-making harder and, over time, may contribute to a disconnect from reality.

Researchers at MIT have identified a gene mutation that may play a key role in this problem. In experiments with mice, they found that the mutation disrupts a brain circuit responsible for updating beliefs when new information is received.

The mutation occurs in a gene called grin2a, which had previously been flagged in large genetic studies of schizophrenia. The new findings suggest that targeting this brain circuit could help improve cognitive symptoms associated with the disorder.

"If this circuit doesn't work well, you cannot quickly integrate information," says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT. "We are quite confident this circuit is one of the mechanisms that contributes to the cognitive impairment that is a major part of the pathology of schizophrenia."

Feng and Michael Halassa, an associate professor of psychiatry and neuroscience at Tufts University, are the senior authors of the study, which appears in Nature Neuroscience. Tingting Zhou, a research scientist at the McGovern Institute, and Yi-Yun Ho, a former MIT postdoc, are the lead authors.

Genetic Clues and Schizophrenia Risk

Schizophrenia has a strong genetic component. In the general population, about 1 percent of people develop the condition. That risk increases to 10 percent if a parent or sibling is affected, and rises to 50 percent for identical twins.

Scientists at the Stanley Center for Psychiatric Research at the Broad Institute have identified more than 100 gene variants associated with schizophrenia through genome-wide association studies. However, many of these variants are located in non-coding regions of DNA, making their effects difficult to interpret.

To address this, researchers used whole-exome sequencing, a method that focuses on protein-coding regions of the genome. This approach allowed them to identify mutations directly within genes.

By analyzing around 25,000 sequences from people with schizophrenia and 100,000 from control subjects, the team identified 10 genes where mutations significantly increase the risk of developing the disorder.

How a Gene Mutation Alters Brain Function

In the new study, researchers created mice carrying a mutation in one of those genes, grin2a. This gene produces part of the NMDA receptor, which is activated by the neurotransmitter glutamate and is commonly found on neurons.

Zhou then examined whether these mice showed behaviors similar to those seen in schizophrenia. While symptoms such as hallucinations and delusions (loss of contact with reality) cannot be directly modeled in mice, scientists can study related issues like difficulty interpreting new sensory information.

For years, researchers have proposed that psychosis may result from a reduced ability to update beliefs when new information becomes available.

"Our brain can form a prior belief of reality, and when sensory input comes into the brain, a neurotypical brain can use this new input to update the prior belief. This allows us to generate a new belief that's close to what the reality is," Zhou says. "What happens in schizophrenia patients is that they weigh too heavily on the prior belief. They don't use as much current input to update what they believed before, so the new belief is detached from reality."

Experiment Reveals Slower Decision-Making

To test this idea, Zhou designed a task where mice had to choose between two levers to receive a reward. One lever was low-reward -- mice needed six presses to get one drop of milk. The other offered a higher reward, delivering three drops per press.

At first, all mic