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 linked to this issue. In experiments with mice, they discovered that this mutation disrupts a brain circuit responsible for updating beliefs based on new information.
Understanding Gene Mutations in Schizophrenia
The mutation occurs in a gene called grin2a, previously noted in extensive genetic studies of schizophrenia. Findings suggest that targeting this brain circuit could alleviate cognitive symptoms related to the disorder.
“If this circuit doesn’t work well, you cannot quickly integrate information,” states Guoping Feng, a leading researcher at MIT. “We are confident this circuit contributes to the cognitive impairments characteristic of schizophrenia.”
Feng and Michael Halassa, from Tufts University, are the senior authors of the study published in Nature Neuroscience. Tingting Zhou and Yi-Yun Ho led the research efforts.
Genetic Influences on Schizophrenia Risk
Schizophrenia has a significant genetic component. Approximately 1 percent of the general population develops the condition, with risk increasing to 10 percent if a direct relative is affected, and up to 50 percent for identical twins.
At the Stanley Center for Psychiatric Research, over 100 gene variants associated with schizophrenia have been identified through genome-wide association studies. However, many of these variants reside in non-coding regions, complicating their interpretation.
To clarify these associations, researchers employed whole-exome sequencing, focusing on protein-coding regions to identify direct mutations. Analysis of around 25,000 sequences from individuals with schizophrenia and 100,000 from control subjects revealed 10 genes with mutations that significantly heighten the risk of developing the disorder.
How Gene Mutation Influences Brain Processes
The recent study focused on mice with the grin2a mutation, which impacts the NMDA receptor activated by the neurotransmitter glutamate, found on neurons. Zhou examined whether these mice exhibited behaviors akin to those seen in schizophrenia. While mice cannot display hallucinations or delusions, related issues like difficulty in interpreting sensory information can be assessed.
Researchers have long theorized that psychosis may stem from a diminished capacity to update beliefs with new information.
“Neurotypical brains can update prior beliefs when new sensory input arrives,” explains Zhou. “In schizophrenia, patients overly rely on prior beliefs, failing to adequately integrate current input, leading to beliefs detached from reality.”
Behavioral Experiments Reveal Decision-Making Delays
To explore this further, Zhou designed a task where mice selected between two levers for rewards. One lever required six presses for a single drop of milk, while the other delivered three drops per press.
Initially, all mice preferred the high-reward lever. However, as the effort for this option increased, healthy mice adapted their behavior, eventually choosing the simpler option when required efforts became equal.
Conversely, mice with the grin2a mutation exhibited delayed decision-making and fluctuated longer between options before committing to the more efficient choice. “Neurotypical animals made adaptive decisions sooner,” Zhou notes, “while animals with the mutation displayed significantly slower decision-making.”
Identifying Key Brain Circuits
Using functional ultrasound imaging and electrical recordings, researchers identified the mediodorsal thalamus as the brain region most affected by the mutation. This area connects to the prefrontal cortex, forming a thalamocortical circuit vital for decision-making and executive functions.
Neurons within this region appeared to track fluctuations in choice values, showcasing distinct neural activity patterns based on whether mice were exploring options or committing to a decision.
Potential Reversal of Symptoms Through Circuit Activation
The researchers demonstrated the ability to reverse the mutation’s behavioral effects by activating neurons in the mediodorsal thalamus using optogenetics. When activated, these neurons prompted mice to behave more like those without the mutation.
While only a minority of schizophrenia patients possess grin2a mutations, dysfunction in this circuit may represent a shared mechanism for cognitive impairments seen in various patients. Targeting this pathway could pave the way for innovative treatment options, and researchers are currently exploring specific circuit components for potential drug targets.
Funding and Future Research Directions
This research received funding from multiple institutions, including the National Institutes of Mental Health and the Broad Institute. Ongoing investigations aim to further elucidate the complexities of schizophrenia and identify effective therapeutic strategies.