Pat R. Levitt, Ph.D.
Molecular clue for schizophrenia sparks funding
A person with schizophrenia exists in a blur of distorted perceptions and paranoid fears, racing thoughts and erratic emotion—an unanchored reality of unbearable anguish. The drugs given to treat the disease squelch the disembodied voices and monstrous imaginings, but they do little to clear muddled thinking, and they disrupt any chance for normalcy by inducing such side effects as an excessive need for sleep or severe motor problems. Part of the pain of this disease is that current medications are ineffective in treating cognitive deficiencies, a psychic torment that affects one in 100 people, regardless of ethnic or cultural background.
Pat R. Levitt, Ph.D., the new director of the John F. Kennedy Center for Research on Human Development, has some ideas for finding better treatments for schizophrenia. Levitt, who will officially assume directorship in June, has recently been given the Neuroscience of Brain Disorders Award from the McKnight Endowment Fund for his research proposal titled “Molecular Strategies Toward Understanding Schizophrenia as a Disease of the Synapse.” The award provides $100,000 annually for three years in support of the research.
Evidence suggests that schizophrenia is a developmental disorder that unfolds over a lifetime, stemming from a genetic predisposition and events that probably occur very early in life, perhaps even while in utero. The average age of onset of psychotic symptoms is in the early 20s. Levitt and others are trying to figure out why there’s such a delay in expression of the most profound symptoms.
Levitt will use the award to extend the work he began with collaborators at the University of Pittsburgh School of Medicine, where he is currently Thomas Detre Professor of Neuroscience. The researchers used DNA microarray chips to look for changes in gene expression in post-mortem brain tissue from individuals diagnosed with schizophrenia.
Out of nearly 10,000 genes screened, they found a very small percentage that showed changes in expression. Some of the genes encode proteins that regulate the efficiency of how brain cells communicate with one another at a point of contact called the synapse. Levitt proposes that problems with synaptic function may underlie the disease.
“A lot of people think it’s a remarkably puzzling component, that an individual may already have disrupted synaptic communication at 4 or 5, yet that person is not schizophrenic until his or her 20s,” he said. “We hope that this research will give us a handle on how we are dealt a set of cards as a child—genetically and environmentally—which may have profound implications for our mental health as adults.”
Levitt will try to pinpoint whether the changes in the genes they’ve identified are due to inherited mutations, or if exposure to something in the person’s environment caused the alterations, perhaps even the medications given to treat the disease.
Epidemiological evidence suggests a number of factors that may contribute to the development of schizophrenia. Those people born in an urban area are twice as likely to develop the disease. Obstetrical complication is a very high risk factor, and there is evidence that the incidence of influenza in the second trimester of pregnancy is linked.
Retrospective studies and reports from teachers have identified predictive indicators of brain dysfunction present during childhood and adolescence in those individuals who eventually develop schizophrenia. Differences in motor skills—as seen in the use of a hand, for example, or in posture or gait—among affected individuals and their siblings have been documented from viewing home movies. Teachers often characterize children later affected by the disease as somewhat isolated, or socially awkward.
This is not to say that all physically or socially awkward children will develop schizophrenia, Levitt pointed out, just that these behaviors suggest that all is not normal in those children who come to express the disease.
“These traits are subtle and seem to be consistent,” he said. “It’s an indication that something isn’t exactly right.”
Levitt believes that it’s probably not a case of the brain being completely normal, then falling apart. Rather, it’s more likely that events in the brain such as synapse formation and elimination that occur during childhood and adolescence build to a kind of “crescendo,” and that the trigger for expressing the major symptoms might be related to a particularly stressful event. Once schizophrenia has become full-blown, highly stressful situations can cause episodic changes in behavior that can be severe and of significant length.
The effects of the changes in gene expression will be evaluated by introducing mutations of select genes into mice. Levitt will study genetic and functional adaptations in mice in which the expression of these genes has been manipulated singly or in combination, with the goal of identifying specific targets for drug or behavioral therapeutics.
“In the past, the discovery of new treatments for most neuropsychiatric diseases has been hit or miss,” he said. “The field now has the opportunity to place newer and more comprehensive biological strategies behind drug discovery and treatment.”
In preparing and evaluating his mouse models, Levitt will take full advantage of the core research facilities at Vanderbilt, particularly the Transgenic Mouse/Embryonic Stem Cell Shared Resource, directed by Mark A. Magnuson, Ph.D., assistant vice chancellor for Research and professor of Molecular Physiology and Biophysics and Medicine, and the Murine Neurobehavioral Laboratory, directed by Michael P. McDonald, Ph.D., assistant professor of Pharmacology and Investigator and Fellow at the Kennedy Center.
“The core facilities here and the programs that are being developed—bioinformatics, proteomics, mouse genetics, and behavioral profiling—are just first-rate,” he said. “I don’t know this for a fact, but I’m pretty sure the resources here that I described in my application were helpful in getting the award.”
Of the 130 people who sent in letters of intent to the McKnight Foundation, 13 were invited to write a full application, and six final awardees were chosen.
“I am pleased that Pat Levitt has received this well-deserved recognition of his career-long contributions and promise for continued discovery at the interface of genes and the environment in the development of the brain and of behavior,” said Lee E. Limbird, Ph.D., associate vice chancellor for Research. “Vanderbilt is so fortunate that his scientific gifts and scholarship have been recruited to a leadership position as central to trans-university goals in neuroscience as is the Director of the Kennedy Center.”
Levitt’s research on schizophrenia complements the molecular studies of complex neurological brain disorders already in progress at Vanderbilt.
“Pat’s a first-rate neuroscientist and his recruitment places us that much closer to having the critical mass needed for a single institution to tackle complex brain diseases from the bench to the clinic,” said Randy D. Blakely, Ph.D., Allan D. Bass Professor of Pharmacology and director of Vanderbilt’s Center for Molecular Neuroscience and member of the team that recruited Levitt to Vanderbilt. “Pat’s emphasis on early developmental alterations in synapse structure and formation as a prelude to adult onset brain disorders is a timely focus, given what we are now learning about the age-dependent changes in brain structure in schizophrenia.”
Discovering how the brain goes awry in people with serious mental illness, such as schizophrenia, is critical to developing drugs that correct the problem or moderate the consequences. Combining effective medication with psychiatric therapy—and the support of friends and family—could be the formula for prevailing over this devastating disease.