Where the Twain Could Meet
Date: November 2, 2009
It’s enough to make you hold your breath these last few years, watching the certainty creep into our ideas on what makes schizophrenia.
That the disease runs in families is sure. But environment’s role in it has always been a smoking gun: Prenatal exposures to flu, for example, or teenage marijuana use or being born in winter all heighten risk.
Just how, though, is elusive.
Lately, convictions about a gene/environment connection in schizophrenia have tightened, with studies by Hopkins’ Mikhail Pletnikov, M.D., Ph.D., and others playing their part.
Pletnikov began by examining varying genetic strains of rats exposed to a common environmental virus as newborns. Some developed what’s for all intents and purposes rodent schizophrenia. Others were just fine.
Pletnikov took the work further to show that viral infection in the more vulnerable rats touches the same monoamine brain systems as the human disease.
“But as much as the studies with different strains say, yes, genes and environment probably work together to produce schizophrenia,” he explains, “it doesn’t take us far enough.
"You don’t know which genes are important or how environment steps in.”
It’s also difficult to get a handle on the importance of timing.
Does it matter if, say, Borna virus strikes a mother early in pregnancy’s first trimester? Later on? Knowing that is a crucial clue to pathology.
It could guide therapy for a disease that only shadows the brain before birth but doesn’t make itself known until young adulthood.
So recently, when Hopkins colleagues created schizophrenic mice based on a single faulty human gene, Pletnikov’s team was quick to adopt the cleaner, simpler genetic model.
“We have well-founded hope,” he says, “that we can get cell cultures and live animals to show how the environment brings changes to a vulnerable nervous system.”
Pletnikov and Christopher Ross went on to refine the model, making one in which the suspect schizophrenia gene—called DISC1—is inducible.
You can turn mutant DISC1 off by lacing a designer mouse’s food or water with an antibiotic.
“Ultimately,” says Pletnikov, “we hope that will tell us if sensitive periods exist in schizophrenia—times when a primed, developing brain can be derailed by environmental stressors.”
If the “prime time” is between birth and adolescence, the thinking goes, then perhaps blocking or heading off the stressor would also head off the disease.
“It’s not very likely that everything is set in stone before birth,” Pletnikov says. “But we don’t know how plastic these things are in infant mice or humans. This model will help us figure that out.”
The Hopkins scientists have been laying groundwork for timing research. They’ve measured baselines by comparing mutant DISC1 mice and healthy animals after both were exposed prenatally to a virus-mimicking agent.
As expected, definite differences exist.
Studies that vary when DISC1 is expressed come next.
“We have ambitious plans for this model,” says Pletnikov.
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