UCLA Scientists Unveil Molecular Approach to Fight Schizophrenia

UCLA scientists have reported that the discovery of DNA sequence variations associated with increased risk for schizophrenia, impairments in short- and long-term memory, and other cognitive deficits.

"I hope this is the opening salvo in a new molecular approach to fighting schizophrenia," said Tyrone D. Cannon, UCLA's Staglin Family Professor of Psychology, Psychiatry and Human Genetics.

"If we're able to identify people at risk for the illness through sequence variations in genes and know what biochemical pathways are affected by those variations, we're much closer to the day when we can finally prevent schizophrenia."

Cannon and his colleagues report genetic variations on chromosome 1, the largest human chromosome, in two regions of a gene known as DISC1, that are predictive of schizophrenia, neurocognitive deficits, memory impairment, and reductions of gray matter density in the brain's frontal lobes and hippocampus.

They found sequence variations within the DISC1 gene that relate to features associated with the underlying neural basis for schizophrenia. The research is published in the November issue of the Archives of General Psychiatry.

Cannon and his colleagues identified a sequence variation - in a region partly in DISC1 and partly in the neighboring TRAX gene - that occurs in only 1 percent of the population, but in 10 percent of schizophrenia patients, who have the nucleotide sequence "A, A, T, G," rather than the healthy version, "C, C, T, G".

People with this sequence abnormality have reduced gray matter in the frontal cortex, part of the brain implicated in schizophrenia, said Cannon, who is director of UCLA's Staglin Family Music Festival Center for the Assessment and Prevention of Prodromal States, and of UCLA's Center for Cognitive Neuroscience.

"If you have that sequence, your risk for having schizophrenia is greatly increased, by a factor of 10," Cannon said.

He offers an analogy to illustrate the progress of the research. "A crime has been committed, and the SWAT team has encircled the neighborhood, which is DISC1," Cannon said.

"Now we have identified the address and we think we have found the murder weapon. It's only a matter of time before we have the suspect handcuffed on the lawn."

"The genetics of schizophrenia has progressed much more rapidly in the last two or three years than it had in the prior 50," added Cannon, who is also a research scientist at the UCLA Semel Institute of Neuroscience and Human Behavior.

The researchers studied 230 twins in Finland. In some of the pairs, both twins have schizophrenia; in others, one has schizophrenia; and in half of the twins, neither has schizophrenia.

"We have identified particular sequence variations that could be genotyped in any individual," said Cannon, who is hopeful the research will lead to a treatment that could fix the protein.

For example, it is possible that turning "A, A, T, G" to the healthy "C, C, T, G" sequence would result in a normally functioning DISC1 protein, he said.

While schizophrenia patients appear not to have fewer neurons in the brain, the neurons make fewer and weaker connections in regions that synthesize information, Cannon said.

"DISC1 is a strong candidate for explaining some of the cellular pathology that we see in postmortem studies, that in turn appears as reduced gray matter on MRI scans," he said.

"This gene participates in the development and maintenance of synaptic connectivity in the frontal brain region that is very important for integrated cognition."

"We're showing that a fundamental mechanism is broken for producing the connectivity between brain cells," Cannon added.

"This suggests that in schizophrenia patients, their brain plasticity is broken. This is a different way of thinking about the illness at the cellular level."

In his crime analogy, the murder weapon is how DISC1 adversely affects "neural scaffolding" and results in a reduction of connectivity between brain cells.

Future research goals include confirming that the genetic variation affects the cellular connectivity in the brain, and discovering whether that cellular connectivity can be rescued.

DISC1 is a susceptibility gene for schizophrenia, and there are probably several others that have yet to be identified, Cannon said.

Cannon led a team of UCLA scientists who in 2002 reported using a three-dimensional mapping technique to identify regions of the brain where people with schizophrenia have significantly less gray matter than their identical twins and the rest of the population.

Schizophrenia patients have significant reductions of gray matter in regions of the brain that integrate, interpret and organize information, Cannon and his colleagues reported in the Proceedings of the National Academy of Sciences (March 5, 2002).

In previous research, Cannon has identified the fundamental importance of genetic factors, showing that schizophrenia is 80 percent genetic, and that the environmental influences most likely depend on genetic factors as well.

"I envision a day when schizophrenia ceases to be a debilitating disease," Cannon said.

"Our goal is effective early intervention. Our psychological and pharmacological interventions are designed to reduce the likelihood of an initial psychotic episode, decrease the severity and chronicity of psychotic illness, and increase social functioning and the likelihood of stable employment."