A single-nucleotide mutation in a portion of the gene encoding glutamate receptor-3 is associated with a pattern of poorer verbal and cognitive performance that is associated with schizophrenia, suggesting that the mutation is a genetic risk factor for the disease, according to an article in the August 9th issue of the Proceedings of the National Academy of Sciences.

The finding confirms the gene responsible for management of glutamate levels in synapses may play a role in genetic risk for the disease. The amount of glutamate
remaining in the synapse (based on receptor function) may have a downstream impact on cognition.

“Because of the small effects of individual genes in complex genetic disorders like schizophrenia, it is difficult to make significant associations with any one particular marker. However, this study brings us closer to unlocking the genetic clues that increase the risk for schizophrenia,” said Thomas R. Insel, MD, of the National Institutes of Health.

Many of the genes already identified as likely candidates for the disorder have been thought to affect the glutamate system. The current study implicates the glutamate receptor-3 gene as well.

Through alterations in glutamate transmission, the receptor alters brain physiology and cognition, increasing the risk for schizophrenia. To pinpoint the section of the gene responsible for these changes, scientists are exploring a region the single-nucleotide polymorphism called SNP4. The allele containing adenine is more common in people with schizophrenia. In postmortem studies, brains with the A-containing allele have lower levels of N-acetylaspartate, a protein that regulates intracellular levels of glutamate.

In studies with people who have schizophrenia, are healthy siblings, or are healthy volunteers, researchers found that the presence of the A-containing allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. People who had the G-containing allele had relatively more efficient processing in the prefrontal cortex, scoring higher on verbal and cognitive tests than people who are homozygous for the A-allele. The gene seems to affect the mechanism of memory encoding only because there was no genotype effect seen during retrieval in the memory tests.

The researchers believe the less common G-containing allele may exert a protective effect against the disease. It is unclear why the higher-risk A-containing allele is more common in humans. Researchers speculate that it may provide a counterbalancing advantage of some sort, perhaps related to reduced glutamate in the cells.