Key Discovery

MIT neuroscientists have identified a gene mutation, grin2a, that appears to contribute to a schizophrenia symptom: difficulty incorporating new information about the world. The mutation impairs the function of a brain circuit responsible for updating beliefs based on new input, potentially leading to struggles with decision-making and detachment from reality.

This research suggests that drugs targeting this specific brain circuit could help address some cognitive impairments observed in schizophrenia patients.

Research Uncovers Genetic Link and Impaired Adaptation

Schizophrenia is known to have a strong genetic component. Researchers at the Stanley Center for Psychiatric Research previously identified grin2a among 10 genes where mutations significantly increase the risk of developing schizophrenia, using whole-exome sequencing.

In the current study, a mouse model was created with a mutation in grin2a, which encodes a protein forming part of the NMDA receptor. Researchers investigated whether these mice displayed behaviors relevant to schizophrenia symptoms, particularly an impaired ability to update beliefs based on new sensory input.

A behavioral experiment required mice to choose between two levers for a food reward, where one lever's reward value gradually decreased. While healthy mice adaptively switched to the low-reward lever when values equalized, mice with the grin2a mutation took significantly longer to switch, demonstrating slower adaptive decision-making.

Targeting a Key Brain Circuit

Functional ultrasound imaging and electrical recordings revealed that the mediodorsal thalamus was significantly affected by the grin2a mutation. This brain region connects with the prefrontal cortex, forming a thalamocortical circuit vital for cognitive functions like executive control and decision-making.

Neuronal activity in the mediodorsal thalamus appeared to track changes in reward value. Crucially, researchers used optogenetics to activate neurons in the mediodorsal thalamus of mutated mice, which successfully reversed their impaired decision-making behaviors.

Broader Implications for Schizophrenia Treatment

Although mutations in the grin2a gene are rare among schizophrenia patients, the identified circuit dysfunction may represent a converging mechanism for cognitive impairment in a subset of patients with various underlying causes.

The findings suggest that targeting this specific circuit could offer new avenues for developing treatments to overcome cognitive impairments associated with schizophrenia.