A common feature of schizophrenia is difficulty using new information to make sense of the world. This challenge can make decision-making difficult and, over time, lead to a disconnect with reality.
MIT researchers have identified a genetic mutation that may play a key role in this problem. Experiments in mice found that this mutation disrupts the brain circuitry that updates beliefs when new information is received.
The mutation occurs in a gene called grin2a, which was previously identified in large-scale genetic studies of schizophrenia. New findings suggest that targeting this brain circuit may help improve cognitive symptoms associated with the disorder.
“If this circuit doesn’t work well, you can’t integrate information quickly,” says Guoping Feng, the James W. and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT, a member of the Broad Institute at Harvard and MIT, and associate director of the McGovern Institute for Brain Research at the Massachusetts Institute of Technology. “We believe that this circuit is one of the mechanisms contributing to the cognitive deficits that are a key part of the pathology of schizophrenia.”
Fenn and Michael Harassa, an associate professor of psychiatry and neuroscience at Tufts University, are senior authors of the study. natural neuroscience. Tingting Zhou, a researcher at the McGovern Institute, and Yiyun Ho, a former MIT postdoctoral fellow, are lead authors.
Genetic clues and risk of schizophrenia
Schizophrenia has a strong genetic component. In the general population, about 1 percent of people develop this condition. The risk increases to 10 percent if a parent or sibling is affected, and to 50 percent for identical twins.
Scientists at the Broad Institute’s Stanley Psychiatric Research Center have identified more than 100 genetic 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, the researchers used whole exome sequencing, a method that focuses on protein-coding regions of the genome. This approach made it possible to directly identify mutations within genes.
By analyzing around 25,000 sequences from schizophrenia patients and 100,000 sequences from control subjects, the team identified 10 genes whose mutations significantly increase the risk of developing the disorder.
How genetic mutations change brain function
In the new study, researchers created mice with mutations in one of those genes, grin2a. This gene is activated by the neurotransmitter glutamate and produces some of the NMDA receptors commonly found on neurons.
Zhou then investigated whether these mice exhibited behaviors similar to those seen in schizophrenia. Although symptoms such as hallucinations and delusions (loss of contact with reality) cannot be modeled directly in mice, scientists can study related issues such as difficulty interpreting new sensory information.
Researchers have long proposed that psychosis may result from a reduced ability to update beliefs when new information becomes available.
“Our brains can form prior beliefs about reality, and when sensory input enters the brain, the neurotypical brain can use this new input to update previous beliefs. This allows it to generate new beliefs that are closer to reality,” Zhou says. “What happens with people with schizophrenia is that they place too much weight on their previous beliefs. They use less current input to update what they previously believed, so their new beliefs become disconnected from reality.”
Experiments show that decision-making becomes slower
To test this idea, Zhou designed a task in which mice had to choose between two levers to receive a reward. One lever had a low reward and the mouse needed to press it six times to get one drop of milk. The other offered a higher reward, offering three drops per press.
Initially, all mice preferred the higher reward option. However, over time, the effort required for that option gradually increased, but the reward remained low.
Healthy mice adjusted their behavior in response to changing conditions. When the higher-reward option required the same amount of effort as the lower-reward option, they eventually switched and stayed with the easier option.
Mice with the grin2a mutation behaved differently. They kept going back and forth between options for a long time and were slow to commit to more efficient choices.
“We found that neurotypical animals make adaptive decisions in this changing environment,” says Professor Zhou. “They can switch from high reward to low reward around the equivalence point, but that switch happens much slower in the mutant animals. Their adaptive decision-making is much slower than in wild-type animals.”
Identifying important brain circuits
Using functional ultrasound imaging and electrical recordings, the researchers identified the medial dorsal thalamus as the brain region most affected by the mutation. This area is connected to the prefrontal cortex and forms thalamocortical circuits that support decision making and executive control.
Neurons in the medial dorsal thalamus appear to track changes in the values of different choices. The researchers also observed different patterns of neural activity depending on whether the mice were exploring options or making a decision.
Reversing symptoms by activating circuits
The researchers also demonstrated that the behavioral effects of the mutation could be reversed. They used optogenetics to manipulate neurons in the medial thalamus to respond to light. Once these neurons were activated, the mice began to behave more like mice without the mutation.
Although only a small proportion of schizophrenia patients have mutations in grin2a, researchers suggest that dysfunction in this circuit may represent a common mechanism underlying cognitive impairment in some patients.
Targeting this pathway could open new therapeutic possibilities. The research team is now working to identify specific components within the circuit that could be targeted by drugs.
Funding and future direction
This research was funded by the National Institute of Mental Health, the Massachusetts Institute of Technology Poitras Center for Mental Disorders Research, the Massachusetts Institute of Technology Yang Tan Collective, the Massachusetts Institute of Technology K. Lisa Yang and Hock E. Tan Molecular Therapy Center, the Massachusetts Institute of Technology Stelling Family Research Fund, the Stanley Psychiatric Research Center, and the Brain and Behavior Research Foundation.
