Researchers at MIT report that a mutation in the gene GRIN2A may interfere with how the brain updates beliefs when new information arrives, a cognitive difficulty often seen in schizophrenia. In mouse experiments, the change was tied to slower, less adaptive decision-making in a shifting environment.<\/p>\n
Schizophrenia affects about 1% of people and has a strong genetic component, though the biology connecting risk genes to symptoms has been hard to pin down. Large genomic studies have identified many associated variants, but many sit in non-coding DNA, making their functional impact difficult to interpret.<\/p>\n
To narrow in on mutations that directly alter proteins, the team drew on large-scale exome sequencing that compares protein-coding regions across people with schizophrenia and unaffected controls. That work has helped highlight a smaller set of genes where rare disruptive mutations can substantially increase risk.<\/p>\n
GRIN2A stands out because it encodes a subunit of the NMDA receptor, a key component of glutamatergic signaling involved in learning, plasticity and cognitive control. NMDA receptor dysfunction has long been considered relevant to schizophrenia, but linking specific mutations to circuit-level effects has remained challenging.<\/p>\n
In the study\u2019s behavioral task, mice chose between two levers with different reward sizes and different effort costs that changed over time. Typical mice shifted to the more efficient option once the higher-reward choice became too costly, reflecting flexible updating as conditions evolved.<\/p>\n
Mice carrying the GRIN2A-related mutation took longer to commit, continuing to alternate between choices after the balance of effort and reward had effectively changed. The researchers interpret the pattern as reduced ability to incorporate new evidence quickly, leaving prior expectations to dominate behavior for longer.<\/p>\n
Brain measurements pointed to altered activity in the mediodorsal thalamus and its connections with the prefrontal cortex, a pathway central to executive function and decision-making. The team reports that this thalamocortical circuit appeared to represent changing option values differently in the mutated mice.<\/p>\n
Using optogenetics to activate neurons in the mediodorsal thalamus, the researchers were able to push behavior toward the more adaptive pattern seen in control animals. While only a subset of patients would be expected to carry GRIN2A mutations, the results suggest the same circuit could contribute to cognitive symptoms across broader groups.<\/p>\n
The authors frame the work as a step toward treatments that target cognition, an area where many patients continue to experience impairment even when hallucinations or delusions are reduced. Next efforts focus on identifying druggable nodes in the thalamus\u2013prefrontal pathway that might restore more flexible updating without invasive methods.<\/p>\n","protected":false},"excerpt":{"rendered":"
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