Gene Mutation Disrupts Brain Circuit in Schizophrenia
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- MIT researchers, led by Guoping Feng and Michael Halassa, pinpointed a mutation in the grin2a gene as a driver of impaired belief-updating in schizophrenia, publishing their findings in Nature Neuroscience.
- The grin2a mutation disrupts neurons in the mediodorsal thalamus, the region most affected in functional ultrasound and electrical recordings, weakening the thalamocortical circuit that links sensory input to updated beliefs.
- Mice carrying the mutation took significantly longer to switch from a high-effort, high-reward lever to an easier low-reward option when effort costs rose, while healthy mice switched around the equal-value point.
- Optogenetic activation of mediodorsal thalamus neurons in the mutant mice reversed the rigid-choice behavior, restoring adaptive decision-making to near-wild-type levels.
- The grin2a gene encodes part of the NMDA glutamate receptor and was identified after whole-exome sequencing of roughly 25,000 schizophrenia patients and 100,000 controls flagged 10 genes with significant risk mutations.
- Researchers cautioned that grin2a mutations affect only a small fraction of schizophrenia patients, but suggested mediodorsal thalamus dysfunction could be a shared circuit-level mechanism worth targeting with drugs.
- Lead author Tingting Zhou framed the deficit as patients 'weighing too heavily on the prior belief' and failing to integrate current sensory input, producing beliefs that drift from reality.
Why it matters: Schizophrenia's cognitive symptoms — difficulty adapting thinking when circumstances change — currently lack targeted treatments, and the team's reversal of the deficit with optogenetics in mice points the drug-discovery effort at a specific thalamocortical circuit rather than the whole brain. The work also shows that a mutation in a single NMDA-receptor gene can derail belief updating, strengthening the long-debated glutamate hypothesis of schizophrenia.
