Schizophrenia Possibly Linked To Early Brain Development

Writing in the July issue of Biological Psychiatry, Dr. Anthony-Samuel LaMantia, associate professor of cell and molecular physiology at the UNC-CH School of Medicine, for the first time brings together compelling interdisciplinary findings, including new research from his laboratory, to support a neuro-developmental theory of schizophrenia.

"The idea of schizophrenia developed over the last 10 years is there's an early insult in the first trimester of pregnancy that basically pushes brain development in a somewhat aberrant direction," he said.

LaMantia's work focuses on the flow of genetic instructions telling cells exactly where to position themselves to form the embryonic forebrain. This is the front part of the brain from which the cerebral cortex and adjacent brain regions arise. These regions include the basal ganglia, which controls movement; the hippocampus, which is important for memory; and the olfactory bulb.

"We found that to put those major brain regions in the right places you need 'inductive interactions' to set up the identity of cells, dictate which are supposed to be next to one another and impose a basic organization," LaMantia explained.

The UNC-CH researcher has studied disruptions in these genetic instructions; specifically, in the retinoic acid signaling pathway. Retinoic acid is the acid form of vitamin A and, said LaMantia, "a major molecular player" in forebrain formation. It also is important for the proper patterning of the limbs, face and heart.

"Retinoic acid is a signaling molecule in inductive interactions," he said. "It modulates gene expression and is thought to play a central role in embryonic development."

LaMantia has studied forebrain development in the mouse, largely because of its similarity to the human forebrain. He has identified abnormalities in mouse embryos that result from disruptions of the retinoic acid signaling pathway. He and other scientists also have reported craniofacial, heart and limb malformations after such disruptions and from fetal exposure to retinoic acid.

On the human side of the equation, there is retinoid embryopathy. Here, similar malformations occur in newborns whose mothers use retinoid drugs, including Accutane for acne, during the first trimester of pregnancy or who take excessive amounts of vitamin A.

In his article, LaMantia pointed out that the malformation patterns associated with experimental retinoic acid fetal exposure or with signaling pathway disruption also resemble a human genetic disorder called velo-cardio-facial syndrome (VCFS). This syndrome is tied to a gene deletion on chromosome 22.

"Children with this syndrome have limb malformations affecting the digits and some combination of minor craniofacial anomalies involving the eyes, nose and jaw," he said. "They also have a high frequency of early-onset schizophrenia. And if you look at a child who has retinoid embryopathy and one who has VCFS, they look similar. The facial signs and limb signs are identical."

In addition, studies have found a higher incidence of minor physical anomalies of the head, eyes, ears, mouth, hands and feet in schizophrenics than in other individuals.

Even more striking, said LaMantia, is a study at the National Institutes of Health. Among children who met stringent criteria for the diagnosis of childhood schizophrenia, 40 percent had the same gene deletions on chromosome 22. These children also were diagnosed with VCFS.

And while not all VCFS children will develop schizophrenia, most show a range of cognitive, behavioral and psychiatric disorders.

"The data has become compelling that the basic process of forebrain development is a cellular point of vulnerability for potential behavioral and psychiatric disorders, including schizophrenia," LaMantia said. "And if the developing brain is vulnerable to some pathogenic insult during this critical period, what is it?"