Evidence Builds For Glutamate Link to Schizophrenia

During the last decade of the 20th century, it became increasingly apparent that glutamate, not dopamine, is probably the major nerve-transmitter culprit in schizophrenia—and this in spite of the fact that the level of dopamine activity is known to be markedly higher in the brains of schizophrenia patients than in the brains of healthy persons and to be strongly linked with the positive symptoms of schizophrenia.

In other words, it started to look increasingly as if glutamate might do the initial dirty work in the brain as schizophrenia develops, then bring dopamine in on the act. Or as Jack Gorman, M.D., a professor of psychiatry at Columbia University, put it at APA’s 2000 annual meeting, an underdevelopment of glutamate-using neurons might cause an overabundance of dopamine-containing neurons, which then would unleash schizophrenia symptoms (Psychiatric News, July 7, 2000).

Now that the 21st century has arrived, the case continues to build that glutamate and company are heavily involved in schizophrenia. Take, for instance, three new studies reported in the September American Journal of Psychiatry.

David Lewis, M.D., a professor of psychiatry and neuroscience at the University of Pittsburgh, and coworkers measured, in postmortem brain tissue taken from 20 persons with schizophrenia, the amount of a putative marker for glutamate. The team used neurons that originate in the thalamus area of the brain and terminate in the prefrontal cortex.

They also measured the amount of the marker in postmortem brain tissue taken from 20 healthy controls and compared that amount with the amount in the tissue from the schizophrenia subjects. They found less of the marker in tissue from individuals with schizophrenia than in tissue from controls, implying that a paucity of glutamate-using neurons, at least in the thalamus and prefrontal cortex regions, might be implicated in schizophrenia.

Robert E. Smith, M.D., Ph.D., a resident at the University of Michigan’s Psychiatry Residency Research Branch, and his colleagues focused on three proteins that are used for reuptake of glutamate by brain neurons. They compared the genetic expression of these proteins in postmortem brain tissue taken from 12 persons with schizophrenia with that in postmortem brain tissue from eight healthy controls. The tissue came from the thalamus region.

The investigators found greater genetic expression for two out of three of the proteins in tissue taken from the individuals with schizophrenia than in tissue taken from the healthy controls, implying that excessive genetic expression of the proteins, at least in the thalamus, might underlie schizophrenia.

In addition, Stella Dracheva, Ph.D., a professor of psychiatry at Mount Sinai School of Medicine, and her colleagues compared the genetic expression of three different subunits of NMDA receptors in postmortem brain tissue taken from 26 persons with schizophrenia with the expression of the subunits in postmortem brain tissue taken from 13 healthy controls and with the expression of the subunits in postmortem brain tissue taken from 10 people with Alzheimer’s disease. The NMDA receptor is one of the neuron receptors for glutamate; NMDA stands for N-methyl-D-aspartate.

The tissue samples came from the prefrontal cortex and occipital cortex regions of the brain.

Expression for two of the three subunits, the investigators reported, was higher in tissue from people with schizophrenia than in tissue from both healthy controls and Alzheimer’s subjects, suggesting that excessive genetic expression of these two subunits, at least in the prefrontal cortex and occipital cortex regions, might be involved in schizophrenia.

How all these findings fit together and how they might mesh with previous discoveries on the subject is far from clear at this point. For instance, how might the finding from Dracheva and her team that there is excessive NMDA receptor gene expression in schizophrenia be reconciled with a report in the June 1, 2000, Journal of Neuroscience that antipsychotic drugs enhance the function and consequent gene expression of NMDA receptors?

Nonetheless, schizophrenia investigators remain optimistic that all the pieces will ultimately fit together and give a coherent picture of the origins of schizophrenia. For instance, Carol Tamminga, M.D., a professor of psychiatry at the University of Maryland, wrote in an editorial accompanying the study reports that emerging results “will be the basis not only for understanding the pathophysiology of schizophrenia, but also for postulating novel drug targets.” And in a review of the subject that accompanies the study reports, Donald Goff, M.D., and Joseph Coyle, M.D., professors of psychiatry and neuroscience at Harvard University, concluded: “Dysfunction of glutamatergic neurotransmission may play an important role in the pathophysiology of schizophrenia, especially of the negative symptoms and cognitive impairments associated with the disorder, and is a promising target for drug development.”

The study reports, editorial, and review mentioned in this article can be read online at www.ajp.psychiatryonline by searching under the September issue. ▪