Gene responsible for management of glutamate is a promising candidate in determining risk for schizophrenia

Aug 11 2004

Researchers at the National Institute of Mental Health have identified a relationship between a small section of one gene, the brain chemical messenger glutamate, and a collection of traits known to be associated with schizophrenia.

The finding confirms the gene responsible for management of glutamate is a promising candidate in determining risk for schizophrenia. The study, conducted by Michael Egan, M.D., Daniel Weinberger, M.D., and colleagues, is published in the August 9, 2004, of the Proceedings of the National Academy of Sciences.

Glutamate is a key neurotransmitter long thought to play a role in schizophrenia. The gene identified in this study makes the glutamate receptor (GMR3) which is responsible for regulating glutamate in synapses — spaces in between brain cells — where chemicals like glutamate transfer information from cell to cell. The amount of glutamate remaining in the synapse 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 NIMH Director Thomas R. Insel, M.D.

Researchers know that schizophrenia affects several regions in the front part of the brain that are involved in higher order thinking and decision-making and neurotransmitter systems like glutamate. Many of the genes already identified as likely candidates for the disorder have been thought to affect the glutamate system. The study implicates the GMR3 gene as well.

GRM3 alters glutamate transmission, 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 where the gene may differ by one letter at a location called SNP4. The normal variation is spelled with either an 'A' — the more common of the two — or a 'G'. Patients with schizophrenia are more likely to inherit an 'A' from either parent, indicating the 'A' variant slightly increases risk. The 'A' variant is also associated with the pattern of traits linked with the disorder. This was true in patients, their healthy siblings, and normal volunteers.

In the study, people with an 'A' variant have differences in measures of brain glutamate. In a postmortem study of brain tissue, the 'A' variant was associated with lower levels of the chemical that promotes gene expression for the protein responsible for regulating the level of glutamate in the cell. N-acetylaspartate, a measure of cell health evaluated through the use of MRI spectroscopy, was lower in 'A' participants. 'A' carriers had poorer performance on several cognitive tests of prefrontal and hippocampal function than people with the 'G' variant. The 'G' marker was associated with relatively more 'efficient' processing in the prefrontal cortex. Those who inherit the 'G' variant scored higher on verbal and cognitive tests than those who have two of the 'A' variant. Scientists think the less common 'G' variant may exert a protective effect against the disease.

People with schizophrenia and their healthy siblings share the inefficient brain physiology, and cognition patterns, which suggests a link to genetic risk, though the disease itself is most likely caused by a combination of genetic and environmental factors. The gene seems to affect the mechanism of memory encoding only as there was no genotype effect seen during retrieval in the memory tests.

Although scientists could not be certain that the 'A/G' difference accounts for all the affects on brain function, there may be yet undiscovered variations located near SNP4 on the GRM3 gene. It is unclear as to why the higher-risk 'A' variant is more common in humans. Researchers speculate that it may provide a counterbalancing advantage, perhaps related to reduced glutamate in the cells.