Inside Out: Looking at schizophrenia’s inner chaos  pg. 6

“We found that in one of those genes, rgs4, there are some polymorphisms — differences in gene sequences—that are found more prominently in people with schizophrenia than those without,” says Levitt. “What we’re trying to do now is to figure out whether the changes we see in our microarray studies are primary to the disorder or whether they actually reflect an adaptive state—an attempt by neurons to compensate for the principal defect.”

“What’s been striking to us is that the components of the prefrontal cortex that we knew were likely to be important for working memory activity appear to be those that are preferentially disturbed,” adds Lewis. “And other components, which seem to be playing different roles in the prefrontal cortex, are relatively preserved.”

Studies of brain tissue from schizophrenia patients show fewer neurons extending into the prefrontal cortex from the thalamus, a brain region that serves as a processing center for sensory impulses. In addition, communication among neurons is impaired, due to reduced synaptic connections and a lower density of dendritic spines, the nubs on neuronal cell bodies whose job it is to receive thalamic input.

Lewis’ lab has discovered further surprising detail about the prefrontal cortex neurons: A subset that connects with a distinct population of inhibitory neurons has an altered receptor for GABA, the major inhibitory neurotransmitter in the brain. Lewis is designing a clinical trial to evaluate a new drug targeted at this altered receptor.

“To me, what is exciting is to start with very basic science—how the prefrontal cortex normally mediates working memory—then to go to the illness and ask what’s wrong with that circuitry, and in the context of that find an alteration that might be druggable,” he says. “We’ll see in the initial clinical trial whether there’s any evidence of cognitive improvement.”

Translational research

This kind of systematic application of scientific method to the goal of drug discovery is an important aspect of what is called translational research, and it’s the bailiwick of P. Jeffrey Conn, Ph.D., professor of Pharmacology and director of the Vanderbilt Program in Drug Discovery. Conn, who earned his doctorate in Pharmacology at Vanderbilt, was recruited in 2003 from Merck & Co., Inc., where he headed the company’s schizophrenia drug development efforts.

Conn has been investigating the role of the neurotransmitter glutamate in schizophrenia. Glutamate is the “major workhorse in the brain, affecting virtually every circuit involved in any brain function,” he says. Unfortunately, it’s that broad functioning that makes the neurotransmitter such a difficult drug target — effects of a drug would be seen throughout the central nervous system. So when a new class of glutamate receptors, called the metabotropic glutamate (mGlu) receptors, was discovered, a door to more specific control opened.

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