Source: University Of Illinois At Chicago
Date Posted: Tuesday, March 19, 2002
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Errant Stem Cells May Account For Symptoms Of Schizophrenia

Neural stem cells are a ready supply of new parts for the constant wiring and rewiring of the brain's circuitry as this complex organ responds to environmental stimuli so that we can learn new skills, interpret new data and rethink old ideas.
But if those cells can't migrate to the right place and morph into the right kinds of neural links, our cognitive and psychological functions fail.

Researchers at the University of Illinois at Chicago have found that a protein called reelin, whose function in the adult brain has long been a mystery, is responsible for directing the migration of neural stem cells to the appropriate location in the brain as it adapts to new information. The results of the study are published in the March 19 issue of the Proceedings of the National Academy of Sciences.

"Neural stem cells are the precursors to the variety of cell types found in the brain," said Kiminobu Sugaya, assistant professor of psychiatry and the study's principal investigator. "Triggered by unknown environmental cues or factors, they migrate to specific areas to become a glial cell or a neuron, forming a link in the adult brain's complex neural network."

In the study, human neural stem cells were transplanted into an empty space of the brain, called the ventricle, in normal mice and in mice incapable of producing reelin (called "reeler" mice because of their peculiar gait, a result of their genetic defect).

"In the reeler mice, the stem cells got lost," Sugaya said. "They failed to migrate."

In the normal mice, however, the cells migrated into the hippocampus, the central processing unit of the brain; the olfactory lobes, controlling the sense of smell; and the cerebral cortex, responsible for higher mental activities like learning, memory, perception and problem solving. Once located in those regions, the cells turned into mature cells capable of functioning in the new environs.

"In normal mice we found a beautiful, symmetrical migration and differentiation of the stem cells," Sugaya said.

The findings are significant not only because they clearly identify, for the first time, the role of reelin in the adult brain, but also because they suggest one possible molecular mechanism underlying schizophrenia, a devastating psychiatric illness characterized by a distorted perception of reality, disordered thinking and a flat affect.

In an earlier postmortem study of the brains of schizophrenics, Erminio Costa, a co-author of the present study and scientific director of UIC's Psychiatric Institute, found that the level of reelin was half that in normal human brains. Moreover, in a blind study of 60 brains taken postmortem from individuals diagnosed with severe psychiatric disorders, Costa was able to correctly identify those that came from psychotic patients by testing for levels of reelin.

"Perhaps in schizophrenics, who lack reelin, the brain's stem cells can't find their way to make the appropriate neural connections," said Kiminobu Sugaya, "As a result, perception and thinking may break down."

### Other co-authors of the present study were UIC researchers Hojoong Kim, Tingyu Qu, Virginia Kriho, Pascale Lacor, Neil Smalheiser, George Pappas and Alessandro Guidotti.

The study was funded by the National Institute of Mental Health. Copies of the paper are available online at http://www.PNAS.org/cgi/content/abstract/062698299v1, with movies illustrating the migration of cells in both normal and reeler mice.

For more information on UIC, visit http://www.uic.edu.