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 mice preferred the high-reward option. Over time, however, the effort required for that option gradually increased, while the low-reward lever remained unchanged.
Healthy mice adjusted their behavior as conditions shifted. When the effort required for the high-reward option became comparable to the low-reward option, they eventually switched and stayed with the easier choice.
Mice with the grin2a mutation behaved differently. They continued switching back and forth between the options for longer and delayed committing to the more efficient choice.
“We find that neurotypical animals make adaptive decisions in this changing environment,” Zhou says. “They can switch from the high-reward side to the low-reward side around the equal value point, while for the animals with the mutation, the switch happens much later. Their adaptive decision-making is much slower compared to the wild-type animals.”
Key Brain Circuit Identified
Using functional ultrasound imaging and electrical recordings, the researchers identified the mediodorsal thalamus as the brain region most affected by the mutation. This region connects to the prefrontal cortex, forming a thalamocortical circuit that supports decision-making and executive control.
Neurons in the mediodorsal thalamus appeared to track changes in the value of different choices. The researchers also observed distinct patterns of neural activity depending on whether the mice were exploring options or committing to a decision.
Reversing Symptoms by Activating the Circuit
The team also demonstrated that they could reverse the behavioral effects of the mutation. Using optogenetics, they engineered neurons in the mediodorsal thalamus to respond to light. When these neurons were activated, the mice began to behave more like those without the mutation.
Although only a small fraction of schizophrenia patients carry mutations in grin2a, the researchers suggest that dysfunction in this circuit may represent a shared mechanism underlying cognitive impairments in some patients.
Targeting this pathway could open new possibilities for treatment. The team is now working to identify specific components within the circuit that could be targeted with drugs.
Funding and Future Directions
The research was funded by the National Institutes of Mental Health, the Poitras Center for Psychiatric Disorders Research at MIT, the Yang Tan Collective at MIT, the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics at MIT, the Stelling Family Research Fund at MIT, the Stanley Center for Psychiatric Research, and the Brain and Behavior Research Foundation.