What goes wrong in the brain to cause schizophrenia?

There is ample evidence to think that something goes sour in the left temporal lobe and left limbic lobe, and that it involves neurons that use dopamine. Thus one might conclude that some developmental abnormality with dopamine neurons is the ultimate culprit.

Yet recent research indicates that there are even more remote culprits than the dopamine neurons, and they are neurons that use glutamate, rather than dopamine, as a nerve transmitter.

This latest thinking about the biological causes of schizophrenia was presented by Jack Gorman, M.D., a professor of psychiatry at Columbia University College of Physicians and Surgeons in New York City, at APA’s 2000 annual meeting in Chicago in May.

Reductions in the size of the brain have been found over and over in patients with schizophenia, Gorman reported, and the reductions have usually been in the left temporal lobe and the left limbic lobe, not in the right ones. The worse the function in the left temporal lobe in a person with schizophrenia, the more severe the patient’s so-called positive symptoms—hallucinations and delusions. There are also many dopamine neurons, especially those using the D-2 receptor, in the left temporal lobe and the left limbic lobe. What’s more, the level of dopamine activity in the brain is markedly higher in patients with schizophrenia than in healthy persons and is strongly correlated with positive symptoms, and all antipsychotic drugs block, to some extent, the dopamine D-2 receptor. Thus it is more likely than not, Gorman continued, that excess dopamine released in the brain is responsible for hallucinations and delusions, and when antipsychotic drugs work against these particular symptoms, they are doing so by blocking the binding of dopamine to D-2 receptors.

Thus, it would be logical to conclude that a developmental abnormality concerning the dopamine neurons causes schizophrenia, he said. Yet, he pointed out, scientists currently suspect that the cause is not the dopamine neurons per se, but rather a failure to develop glutamate neurons, especially those involving an NMDA (N-methyl-D-aspartate) receptor, and that an underdevelopment of the glutamate neurons then causes overactivity of the dopamine neurons. Research to bolster this suspicion, he added, comes from different quarters.

A researcher at the National Institute of Mental Health, for instance, damaged glutamate neurons in a limbic lobe structure (the hippocampus) in newborn rats. (Newborn rats are comparable in brain development to human fetuses during the second trimester of gestation, a period when things may well go wrong in the brain of a person who later develops schizophrenia.) The rats appeared normal until they entered puberty, then started demonstrating some dopamine-related behavior abnormalities similar to those seen in patients with schizophrenia.

A Duke University investigator reported last year that knocking out the gene for the NMDA receptor produced abnormalities in dopamine function in mice.

Yale University scientists took a drug that blocks the NMDA receptor and showed that when one gives it to mice, it increases dopamine expression in the limbic area. And when Gorman and his colleagues gave human volunteers a drug that blocks the NMDA receptor, it increased dopamine activity in their brains.

So does an underdevelopment of glutamate neurons in the left temporal lobe and left limbic lobe cause an overactivity of dopamine neurons—an overactivity that then unleashes the symptoms of schizophrenia? Gorman thinks so: "We have a coherent story linking glutamate transmission to dopamine abnormalities that explains a great deal of the symptomatic presentation of schizophrenia and gives us real molecular targets for future psychopharmacology."