NIH awards $10.7 million to University of Maryland School of Medicine

The University of Maryland School of Medicine's Maryland Psychiatric Research Center (MPRC), a research center in the School's Department of Psychiatry, was awarded a $10.7 million grant from the National Institutes of Health (NIH) to establish a Silvio O. Conte Neuroscience Research Center that will examine the causes of schizophrenia and search for possible new treatments. Schizophrenia is a devastating psychiatric disease, affecting one percent of people worldwide. Although its roots have been traced to abnormal early brain development, the cause remains a mystery, and current treatments are limited.

The five-year NIH grant*, one of only two awarded this year nationwide, will enable researchers to conduct breakthrough research, combining laboratory and clinical studies of a key chemical called kynurenic acid, a major breakdown product of the amino acid tryptophan. Kynurenic acid levels are increased in the brain of individuals with schizophrenia, and appear to contribute especially to the cognitive abnormalities, which are core symptoms of the disease and a major reason for the inability of people with the disorder to lead productive and fulfilling lives.

"We are extremely proud to receive this prestigious grant from the NIH," said University of Maryland School of Medicine Dean E. Albert Reece, MD, PhD, MBA. "Schizophrenia remains one of the most complex and vexing mental health challenges facing today's medical practitioners and researchers. Our unique combination of laboratory and clinical expertise will open new doors to finding answers—and possibly new treatments—for this debilitating disorder."

Robert Schwarcz, PhD, Director of the MPRC Neuroscience Program, and Professor of Psychiatry, Pharmacology and Pediatrics, is the principal investigator on the NIH grant and will head the Center. Dr. Schwarcz originally identified kynurenic acid in the brain and has investigated its neurobiology for more than 30 years. The Center will be structured into four highly complementary and synergistic projects, ranging from fundamental preclinical research, to studies of cognitive functions in healthy people and in individuals with schizophrenia.

"We are incredibly excited about the award of a Silvio O. Conte Center to MPRC and the opportunity it provides to support innovative translational research on a critically important brain mechanism," said Robert Buchanan, MD, Interim Director of the MPRC. "The proposed research has major implications for the development of new treatment interventions for this severely disabling disorder."

Bankole Johnson, DSc, MD, MPhil, Chair of the SOM"s Department of Psychiatry added: "This award will provide tremendous advances in scientific work as we increase our focus on the study of the brain. We greatly look forward to our involvement in this research, which will have significant benefit to other neuroscience projects on campus."

Specifically, scientists at the new Center will:

• Examine the molecular and cellular mechanisms that normally regulate kynurenic acid production in the animal brain during prenatal development, and explore the long-term effects of increased fetal kynurenic acid formation.
• Investigate the acute and chronic impact of prenatal stress and immune challenges on kyrnurenic acid levels and function in animals. Exposing animals to a second surge of kynurenic acid in adolescence will help evaluate the so-called dual-hit hypotheses of schizophrenia. (In this model, genetic or environmental factors disrupt early central nervous system development. These early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset of schizophrenia symptoms.)
• Study the effects of psychological and other stressors on kynurenic acid metabolism in healthy people and in individuals with schizophrenia, using an array of state-of-the art imaging, electrophysiology and modeling approaches.
• Examine the effects of an acute tryptophan (the chemical precursor of kynurenic acid) in healthy people and those with schiziophrenia on neural circuit and cognitive performance, with functional and chemical neuroimaging measures, neuropsychological assessments and peripheral endocrine and immune markers.

"More than 90 percent of dietary tryptophan is metabolized to kynurenic acid and related compounds. For example, we know that high tryptophan levels from eating holiday turkey can affect our attention, mood and memory," said Dr. Schwarcz. "The close interactions between basic scientists and clinical researchers at the MPRC allow us to conduct critical translational studies in a setting that would be difficult to duplicate elsewhere. We are especially excited to take our hypothesis to the next level of developing and testing specific kynurenic acid synthesis inhibitors in humans. This would allow a breakthrough approach to treat cognitive deficits in people with schizophrenia and, possibly, other brain disorders."

Provided by University of Maryland School of Medicine