UCSF scientists have found a gene in fruit flies whose human equivalent may play a critical role in schizophrenia.

The mutated form of the human gene – one of three associated with schizophrenia – mildly disrupts brain cell signaling.

The gene the study honed in on plays a role in “adaptive plasticity,” the process by which connected cells tolerate wide variations in communication signals. If one cell functions abnormally, the surrounding cells work around it, keeping brain function stable overall.

The team screened 276 mutated, or disabled, fly genes to see whether they affected adaptive plasticity — one, called dysbindin, did.

As reported in the November 20, 2009 issue of Science, senior author of the study, Graeme Davis, PhD, Albert Bowers Endowed Professor and Chair of the Department of Biochemistry and Biophysics at UCSF is quoted as saying:

“Mutation of the gene completely prevented the capacity of the neural circuitry to respond to an experimental perturbation, to be adaptive. The dysbindin mutation was one of very few gene mutations that had this effect,” he says. “The gene’s unique function suggests to us that impaired adaptive plasticity may have particular relevance to the cause or progression of schizophrenia.”

Davis theorizes that normal developmental changes in late teens and early twenties pose considerable stress to ongoing, stable neural function. The capacity of the brain to respond to these normal developmental changes – which reveal themselves as functional variations – may be impaired in people who become schizophrenic.

“The next question the researchers will ask,” he says, “is whether absence of the dysbindin gene causes a blockade of adaptive plasticity in mice and whether other genes linked to schizophrenia cause a similar block of adaptive plasticity.”

The study also ruled out any role in adaptive plasticity of various other genes.

“We tested numerous mutations that alter neural function, and most showed perfectly fine adaptive plasticity.” he says, “This suggests that there are distinct roles for genes at the synapse, some support normal neural function while a small subset control adaptive plasticity.”

“It’s become clear that the nervous system is remarkably stable, but not as one might suspect,” says Davis. “It is continuously responsive to a changing environment, which allows us to learn and remember and to respond to environmental change. There probably are many processes that are sensing the environment, continually updating neural function and neural structure in order to keep the brain stable. If we can understand how stability is maintained in the nervous system, perhaps we could understand what happens when stability is lost and disease ensues.”

“These are big questions that reach far beyond our current understanding of brain function,” he says. “This is the power and importance of basic science. By studying fundamental questions, you can discover unexpected phenomenon and also create new perspectives for understanding existing diseases, even if the human genes are known.” The new finding, he says, “may add a new dimension to the conversation about the origins of schizophrenia.”

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

Related links:
Davis lab: http://biochemistry.ucsf.edu/labs/davis/