Schizophrenia: fetal roots for GABA loss.

Early in some fetal development, cell connections go awry in the outer layer, or cortex, of the brain. By young adulthood, neurons at the front of the cortex that help orchestrate thinking and motivation have trouble communicating with other brain regions. Sluggish activity by cortical cells then leads to cutbacks in a key chemical messenger, further hampering brain function and mental life.

This unfortunate series of developmental disturbances may result in the cerebral malfunctioning responsible for some cases of schizophrenia, according to a report in the April Archives of General Psychiatry. Data now suggest that in many instances of this severe mental disorder, neurons in the adult brain's "prefrontal cortex" lack messenger RNA molecules to carry out genetic instructions for forming an enzyme crucial in making the neurotransmitter known as gamma-aminobutyric acid, or GABA.

"It is possible that the malfunction of the cerebral cortex in adult schizophrenics results from a defect in [fetal] brain development," assert Scharam Akbarian, a neurobiologist at the University of California, Irvine, and his colleagues. Yet because prefrontal cells do not die or dwindle in number when deprived of GABA, the brains of people with schizophrenia look healthy, the investigators contend.

Supporting data for their argument have mounted in the past decade. For instance, Akbarian's group uncovered evidence that schizophrenia involves a loss of fetal brain neurons that bear a protective enzyme (SN: 5/29/93, p.346). These cells are part of the cortical subplate, a temporary gateway to the cortex for migrating fetal neurons.

In their new project, Akbarian and his coworkers studied the brains of 20 deceased adults, 10 of whom had suffered from schizophrenia for at least 18 years and 10 who had been free of psychiatric or neurological disease.

Microscopic analyses focused on slices of tissue from a section of the prefrontal cortex in which, according to previous studies, cell activity slows in people diagnosed with schizophrenia.

Compared to brains from controls, those from people who had schizophrenia contained 30 percent to 48 percent less of the messenger RNA for an important GABA-producing enzyme. The largest of these schizophrenia-related deficits appeared in tissue layers close to the brain's surface.

Still, the total number of prefrontal neurons and the number of distinctively shaped cells known to take part in GABA synthesis were about equal in the two sets of brains, the scientists hold.

A prenatal disturbance of the cortical subplate may interfere with connections between the prefrontal cortex and other brain areas that integrate thought and sensations, such as the thalamus (SN: 10/29/94, p.284), Akbarian's team theorizes. This may eventually lower prefrontal activity enough that specific genes dispatch decreased amounts of the messenger RNA needed for GABA production, in their view.

The findings, although preliminary, may suggest a brain mechanism for the so-called negative symptoms of schizophrenia, such as apathy, emotional flattening, and disorganized thoughts, propose neuroscientists Dennis E. Lee and Allan J. Tobin, both of the University of California, Los Angeles, in an accompanying comment.

Further work is needed to clarify whether prolonged antipsychotic drug treatment of people with schizophrenia contributed to their lower GABA levels, Lee and Tobin add. Antipsychotic injections in mice increase amounts of messenger RNA employed in GABA production. This finding suggests that messenger RNA declines linked to schizophrenia did not result from years of drug treatment, Akbarian and his associates contend.