Inside Out: Looking at schizophrenia’s inner chaos  pg. 7

“The evidence suggested that they could fine-tune activity in glutamate circuits,” Conn explains. “So instead of hitting the circuit with a sledgehammer, it’s a subtle modulation of activity in that circuit.”

Because mGlu receptors are located on both sides of the synapse, they are involved in both sending and receiving messages. That renders them capable of serving as a sort of “dimmer switch,” says Conn, dampening or enhancing transmission in specific brain circuits.

Conn and others are looking at compounds that target mGlu receptors as potential antipsychotic therapeutics. “The goal is to screen tens or hundreds of thousands of small molecules to find compounds that have these actions, to develop them to the point where we can show very specific effects on these glutamate circuits, and then test those compounds to see if they have the effect we predicted,” he says.

Conn also is investigating the role of another neurotransmitter, acetylcholine, in schizophrenia.

Some compounds that target specific cholinergic receptors, including a drug under development by Eli Lilly and Co. to treat Alzheimer’s disease, have been found to have both cognitive and antipsychotic effects.

“This is, I think, one of the most promising new directions in antipsychotic research,” says Conn, “and it’s probably one you haven’t heard a lot about. But this psychosis-cognition interface is why those compounds may stand out in terms of potential anti-psychotic efficacy.”

Conn, Meltzer and their colleagues, Dr. Junji Ichikawa and Zhu Li, Ph.D., in the Psychiatry Department are investigating whether the improvement of cognition by atypical antipsychotics may be related to their ability to trigger acetylcholine release. If so, the connection could lead to the next generation of “cognitive enhancers,” says Meltzer.

Tracking inherited traits

The best chance at cracking schizophrenia’s mysteries may lie not with the people who have it but with their relatives. A significant percentage of first-degree relatives display schizotypal behavior, exhibiting some number of traits common to the disorder—for example, verbal memory or difficulty tracking objects moving through space—but not the more disabling symptoms.

Rather than look for single genes, some researchers are bundling these traits, which they call endophenotypes, and are tracing their occurrence in families affected by the disorder.

The hope is that whatever genes are controlling these endophenotypic markers may lie in close proximity to a gene, or genes, that directly contributes to schizophrenia’s pathophysiology. A similar strategy proved successful in colon cancer, where it was found that the disease is not inherited, but its endophenotype—the tendency to form polyps—is.

Sohee Park, Ph.D., adjusts a device used in a new non-invasive technique called near infrared optical imaging that she uses in her studies of cognitive function.  As research subject Mikisha Doop takes a computerized working memory test, her brain activity will be monitored through the cap-like device and recorded by a second computer.
Photo by Anne Rayner
Three large genetic studies of schizophrenia are already in the works. Two of the studies were launched in 2002 by researchers at the University of Pennsylvania and the University of Pittsburgh. One plans to enroll 150 families, each of which has at least two affected members. The other—the Project Among African Americans to Explore Risks for Schizophrenia—will be a larger study of families in which two siblings have the disorder. The studies will test for attention, working memory, and executive functions, such as organization, problem solving, and decision-making.

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