By David N. Leff

Editor's note: Science Scan is a roundup of recently published biotechnology-related research:

What gene mapping is now — and will be, into the 21st century — "brain mapping" was in the 19th century.

Phrenology, the name of the pseudoscientific discipline, plotted human and animal mental faculties and character traits to sites on the cerebral surface, as evidenced by the size and shape of the skull. Well into the 20th century, circus sideshows exhibited charts of the head, showing areas labeled with dozens of personality traits that range from amativeness, benevolence, combativeness, secretiveness and self-esteem to weight-perception and metaphysical spirit.

At the same time, in the late 1800s, a German neurologist named Korbian Brodmann (1868-1918) systematically delineated 47 areas of the human cerebral cortex. To this day, "Brodmann's areas" are tools for scientists studying the brain's neuronal functions.

Among these researchers is neuropsychiatrist Erminio Costa, at the University of Illinois College of Medicine, in Chicago. He is senior author of a paper in the Dec. 22, 1998 edition of the Proceedings of the National Academy of Sciences (PNAS) titled "A decrease of reelin expression as a putative vulnerability factor in schizophrenia."

"The name reelin," Costa explained, "derives from reeler, referring to the characteristic gaiting behavior of the mouse phenotype that has a null mutation of a gene (reln) with about 450 kilobases, encoding a 3,461-amino acid residue, RELN."

That protein regulates certain neurons in the cerebral cortex, and guides the migration of embryonic cortical neurons to their final destination in the developing brain.

Costa's paper noted that recent postmortem research by others reported "increased neuronal density and reduced cortical volume in Brodmann's areas 9 and 46 with schizophrenia." Separate evidence "suggests that schizophrenia is not exclusively related to either single- or multiple-gene defects," the paper reported.

The fact that adults diagnosed with the disorder were apparently normal as children, Costa pointed out, "has provided support for the hypothesis that schizophrenia etiology may involve a 'two-hit' process."

In this process, the co-authors suggested, "genetic load, adverse embryonic or perinatal events — mother's viral illness, low birth weight, prematurity and brain damage — may be considered a first hit that leads to vulnerability to schizophrenia. Hormonal events during puberty could act as a second hit, facilitating excitotoxicity or oxygen radical formation due to environmental factors."

Against this background, Costa and his co-authors set out to determine the possible role of reeler — gene and protein — in the two-hit model.

Reeler mice, they determined, neither synthesize nor secrete typical RELN protein. In rats, they found that once the embryonic cells responsible for RELN function disappear, a second generation of the protein is expressed in adult brains by neurons in the cortex that secrete GABA (gamma-aminobutyric acid), which is an inhibitor of neurotransmission.

"When we became aware," Costa's paper recounted, "that RELN messenger RNA expression occurs in the adult human brain, we reasoned that if there was a genetic defect in the transcription of RELN mRNA with schizophrenia, a reflection of such abnormality should persist as a generalized deficit of RELN protein expressed in adult brain."

Whereupon, Costa hypothesized that besides the first hit, such a deficit might contribute to the second hit, "which elicits a neuronal dysfunction responsible for the onset of symptoms in schizophrenia."

The co-authors compared mRNA in postmortem brain samples from 18 diagnosed schizophrenics and 18 matched, non-psychiatric controls. RELN mRNA expressed in the latter was higher in the cerebellum than in several Brodmann's cortical areas. In brain areas of schizophrenic patients, this RELN mRNA was decreased by 40 to 50 percent.

That drop, they observed, "is reminiscent of the extent of RELN mRNA decrease observed in the heterozygous reeler mouse.

In one respect, the two cohorts were mismatched. By definition, the non-psychiatric subjects had never taken haloperidol, the standard drug therapeutic for schizophrenia, but all of the psychiatric ones had. So, as an interim strategy, the group injected haloperidol into rats, and found it did not alter the RELN mRNA content in cortex or cerebellum.

"Overall," Costa and his co-authors conclude, "the present findings are compatible with a two-hit neurodevelopmental/vulnerability model of schizophrenia."

Brain Scans Find Similarities Between Schizophrenics And Those At High Risk For The Disease

An entirely separate but relevant article appears in this week's Lancet, dated Jan. 2, 1999, titled, "Magnetic resonance imaging of brain in people at high risk of developing schizophrenia." Its authors are Scottish psychiatrists at the Royal Edinburgh Hospital.

They defined high risk as two or more close relatives with the disorder, scanned the brains of 100 such subjects, and compared them with 20 patients in their first episode of schizophrenia and with 30 healthy controls.

Their "most notable finding" is that a group of people at high risk of developing schizophrenia for genetic reasons have several structural abnormalities of the brain — similar to those in patients with the disorder — before symptoms of the illness appear,

"Genetic predisposition is the most important risk factor that we know of," their paper observed. It cited several studies that showed "relative risks are increased five to 40 times in patients with one or more first-degree relatives, but no strongly linked genes have been identified."

An accompanying editorial noted that the full implications of this study "will not be known for a decade or so, by which time about one in ten of the high-risk individuals will have developed schizophrenia. It will be intriguing to see whether any of the structural [brain] variables predict onset, and, if so, whether the predictive power is of any potential clinical value." *