New research by Foundation-funded scientists sheds light on a problem in brain biochemistry that scientists have previously associated with schizophrenia. The problem concerns the function of a docking port called the NMDA receptor, which is found on a common type of neuron in the brain. Among other things, this receptor is important in the management of memory, since it helps adjust the strength of connections between neurons.

Low activity at the NMDA receptor has previously been associated with schizophrenia and is thought by some to be among its biological causes. Now, research by a team led by 2013 NARSAD Independent Investigator Alessandro Usiello, Ph.D., finds that low levels of a neurotransmitter called D-aspartate might be present in people with schizophrenia and may be contributing to symptoms. The study was published online February 17th in Translational Psychiatry.

The D-aspartate molecule activates NMDA receptors, and is present at high levels in the embryo, while the brain is developing. Its presence rapidly decreases after birth because of the action of an enzyme called DDO (D-aspartate oxidase). Studies in the prefrontal cortex of patients with schizophrenia have shown a decrease in D-aspartate compared to healthy people. Because of these known factors, Dr. Usiello and his colleagues looked at postmortem samples of prefrontal cortex donated by schizophrenia patients. They found evidence of high levels of DDO expression, suggesting that this, along with a decrease in D-aspartate, might be present in those with schizophrenia and contribute to symptoms by reducing the activity of NMDA receptors. Dr. Usiello’s team included Alessandro Bertolino, M.D., Ph.D., a recipient of NARSAD Independent Investigator grants in 1999 and 2013.

To investigate further, the team used genetic methods to create mice that did not produce DDO. Without the enzyme, the mice had high levels of D-aspartate. They were given a drug called phencyclidine that decreases the activity of NMDA receptors. Normally this drug (popularly known as “Angel Dust”) creates effects similar to those seen in people with psychosis. But in this case, the drug’s effects were blunted in genetically modified mice. Why? Increased D-aspartate levels seemed to be the reason. This is consistent with the theory that the opposite condition––abnormally low levels of D-aspartate––could be involved in psychotic and other symptoms seen in schizophrenia.

There is much more work to be done to further define the role of D-aspartate and DDO in the brain. Dr. Usiello plans to further investigate D-aspartate levels during neural development in the embryo to find out whether lowered levels might play a part in the development of schizophrenia.

Read the abstract.