Highlights—That Provide Personal Perspectives of Vanderbilt Disorders Kennedy Center Research, Training, Service, and Philanthropy
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D VVeeRY Number 28 | Spring 2010 | Vanderbilt University This Spring 2010 issue features stories—the one below and four others New Tool for Modeling Brain listed in highlights—that provide personal perspectives of Vanderbilt Disorders Kennedy Center research, training, service, and philanthropy. BY LEIGH MACMILLAN Translational Experiences t’s hard to know if a mouse feels paranoid, hears voices, or I experiences the cognitive symptoms of schizophrenia. So BY EVON BATEY LEE developing a mouse model for this disorder is tricky. But mouse models (or any animal models) of hen I was 9 years old, my family moved from Tennessee schizophrenia and other complex brain disorders are Wto Germany for a year because my father received a precisely what are needed to unravel the pathology of these Fulbright grant to study theology at the University of Tübingen . disorders and find more effective treatments. This journey turned out to have a powerful impact on my Now, Karoly Mirnics, M.D., professor of Psychiatry, development for many reasons. and colleagues have developed a novel strategy to generate One critical factor was that my parents found housing in a mouse models for studying complex brain disorders. They Y L small farming village and enrolled me in the local school— I M used the new tool, described in the journal A Molecular F where I was the only “foreigner .” Other than a few phrases that D N A Psychiatry , to reduce the expression of a gene in a select set E E my father had taught us prior to the voyage across the Atlantic, L N of neurons, to mimic one of the brain deficits observed O V I spoke virtually no German upon arrival , so communication E F in schizophrenia. O Y was a major challenge. S E T “As a field, we came to the conclusion that we can’t R U Besides the language barrier, I was clearly an oddity for O C mimic schizophrenia in a mouse,” said Mirnics, who is also these young German students . It was the early 1960s—just Evon Lee at 9 years old in Germany a VKC investigator. “What we can do is mimic certain after the Berlin Wall was built —but before people had color pathophysiological processes that are related to televisions, the Internet, or instant messaging . My classmates ’ primary exposure to Americans came schizophrenia in humans and then try to put together from watching old westerns on black and white TV . Based on their experience and appraisal of me as a from many different mouse models what is really going slight white girl who wore her hair in long dark braids, one of their initial questions was whether I was on in the human brain.” Continued on page 2 a “Cowboy” or an “Indian .” As we got better acquainted through studying and playing together , I was accepted with amazing kindness and hospitality. Building on Success A Psychologist in a Basic BY JAN ROSEMERGY Science Lab Fast forward four decades when I he Vanderbilt relived this experience of being a “TKennedy Center is stranger in a strange land. Two years doing great—but we could ago I was invited to join a VKC basic be even greater,” said science lab studying the clinical Elisabeth Dykens, Ph.D., genetics of neurodevelopmental and in her first State of the neuropsychiatric disorders. I was Vanderbilt Kennedy Center again an oddity, but this time , rather address as VKC director. than being a grade school student, I She reviewed the Center’s was a middle-aged (no longer past and present success skinny) psychologist who did not Elisabeth Dykens and challenged its speak the technical language of the members to build on that success . basic scientists I was joining. N I The Center’s impressive historical roots are a source P U A I had years of experience as a M Y of strength, Dykens said, pointing to its rich legacy as N O developmental psychologist T the second of the nation’s Eunice Kennedy Shriver performing diagnostic assessments of Intellectual and Developmental Disabilities Research Evon Lee, developmental psychologist and member of a children with developmental Centers (IDDRC) . basic science lab disabilities and interacting with Dykens enumerated the many factors today that professionals from various health-related fields . I had virtually no experience working directly with contribute to the Center’s well-being, chief among them laboratory-based investigators. Despite my complete naïveté in this area, the lab director welcomed me being a university-wide center within Vanderbilt. into this new community and reassured me that I would have something useful to contribute. She also cited supportive, facilitative administration; This new adventure began with my sitting in on research meetings where the next steps of experiments talented, interdisciplinary faculty, trainees, and staff; were being planned and attending conferences where the results of these studies were presented. Because I federal grants that provide the VKC with a stable was a novice and often had no clue about the topic being discussed, I sometimes passed the time by infrastructure; and mission-driven work . scribbling down technical terms to look up later, as well as jokes I wanted to remember . “Our mission is to facilitate discoveries and best Since psychologists often enjoy watching people, I was fascinated on multiple levels to observe this practices that make positive Continued on page 2 enterprise unfold. On one level, the lab itself had a personality that included Continued on page 2 Best Buddies and Next Step Students Rock on Spring Break.........................................4 highlights Growing in Leadership.....................................................................................................8 Horses, Children, and Ministry .........................................................................................9 featuring personal perspectives A Mother’s Crusade for Her Daughter ............................................................................ 10 TRANSLATIONAL EXPERIENCES NEW TOOL FOR MODELING BRAIN DISORDERS from page 1 from page 1 To choose which pathophysiological processes to of the targeted neurons by their fluorescent “glow.” the humor and interactions of the lab members and mimic, the investigators examined gene expression The researchers demonstrated that the new approach their mentoring and shepherding by the lab patterns in postmortem brain tissue from patients with reduced the levels of GAD1 in interneurons that express a director. On another level , there was the integration schizophrenia. Mirnics explained that gene expression protein called neuropeptide Y. They also are targeting of multiple fields of study—cell biology, genetics, patterns reflect the “sum of lifetime events” that have other groups of interneurons, and they are beginning to biochemistry, cognitive neuroscience. It was occurred in the patient’s brain. characterize the new mouse models and define “what intriguing to see how a discovery in one area could “Gene expression is a these neurons do in the brain, and inform or change the trajectory of research convergence point between how the mouse behaves if we in another. genetic and environmental inactivate these neurons,” Mirnics One specific area of interest for the lab was insults,” he said. “We don’t said. autism spectrum disorders (ASD ). I presented exactly know what those insults Using multiple types of animal information about measures that psychologists use to were, but we can see their models, Mirnics hopes the team help make a diagnosis of ASD. This was useful ‘signature.’ If this signature is will be able to “dissect the because the lab had access to a large database that what produces the symptoms functions of these specific included behavioral data linked to genetic of the disease, then that’s what populations of interneurons and information about individuals with ASD, and I could we want to mimic in an how they relate to behavioral explain how the measures were organized and scored. animal model.” deficits in schizophrenia, and The most consistent findings ultimately find drugs that will Lessons Learned in human postmortem brains counterbalance the deficits in Even at the end of the year, I understood only a have been deficits in these neuronal populations.” small portion of the discussions, but this experience “interneurons” that release the The new technology “has led me to explore journals I would never have enormous potential for making inhibitory neurotransmitter Y M R touched before , to search websites I had never heard U GABA, in particular a reduction N animal models because it allows A S U of, and to read books like What’s Wrong with My in the levels of the GABA- S the researcher to target any gene Mouse and Genetics for Dummies . The experience producing enzyme GAD1. Karoly Mirnics, Krassimira Garbett, and for silencing in a cell type also broke down stereotypes I had held about Interneurons are an colleagues are developing new ways to specific way,” Mirnics said. “It’s bench scientists . “integrative force in the brain’s generate animal models to study complex not limited to psychiatry brain disorders. I still have only the most tenuous grasp on cortex—they likely define our disorders, but can be used for these topics, but I experienced a metamorphosis. working memory, which suffers devastating losses in virtually any type of disease model.” The generous acceptance of my ignorance coupled schizophrenia,” Mirnics said. He noted that the new approach is faster and less with the appreciation of what I actually could He and his colleagues decided to systematically costly than mouse knockout technologies, and that it offer —clinical experience with “real” children and reduce GAD1 levels in different populations of offers investigators the advantage of being able to see the families, and knowledge of some of the mouse interneurons. cells that have been targeted (because of the fluorescent psychological assessment tools —promoted a level of To do this, they created a new molecular strategy marker). He also suggested that a single construct could comfort that freed me to ask questions and to share for making a transgenic mouse (a mouse with an include multiple microRNAs to block the expression of my ideas .