TNP Web Site, David A. Lewis M.D., Director

Image description of Translational Neuroscience Program

The overall objective of the Translational Neuroscience Program, directed by David A. Lewis, MD, is to understand the neurobiological basis for complex human cognitive and emotional functions and the manner in which alterations in the brain give rise to the types of disturbances in these functions that characterize certain psychiatric disorders. In pursuit of this goal, Program scientists seek to "translate" clinical observations into hypotheses about the biological mechanisms involved in a disease process that can be tested in the more tractable conditions of the laboratory in order to guide the identification of molecular targets for drug development. Indeed, the principal motivation for these studies is the acquisition of the knowledge needed to develop novel approaches for improving the treatment and prevention of these disorders.

The research strategies utilized by the Translational Neuroscience Program are designed to dissect the disease process of interest. As illustrated in Figure 1 below, we seek to explore how certain etiological factors, or causes of an illness, can unleash pathogenetic mechanisms that produce pathological disturbances in the brain, and how these brain disturbances give rise to the pathophysiological processes that are manifest as a particular clinical syndrome. Understanding pathophysiology is critical to the rational development of new treatments that can reverse these processes, resulting in the amelioration of the signs and symptoms of an illness. Similarly, understanding pathogenesis is essential for the development of secondary forms of disease prevention. Because brain pathology occupies the center point of this series of events, Program research activities have focused on identifying the nature of the brain disturbances in major psychiatric illnesses. These findings are then used to guide investigations into disease pathogenesis and pathophysiology. For example, in our microarray studies of the prefrontal cortex in schizophrenia, we identified a marked and consistent under-expression of the transcript for Regulator of G-protein Signaling 4 (RGS4). Further studies on the function of this protein and the chromosomal location of the RGS4 gene suggested that it might be a susceptibility gene for the illness, a hypothesis supported by ours and other research groups' investigations of the over transmission of certain RGS4 polymorphisms in schizophrenia. In other studies, we detected in individuals with schizophrenia altered levels of gene products in chandelier neurons, a subset of prefrontal cortical GABA neurons, and in their synaptic targets, the axon initial segments of pyramidal neurons. The convergence of these findings suggested a disruption in the prefrontal circuitry responsible for regulating the synchronized neural activity involved in working memory, a critical cognitive process that is impaired in individuals with schizophrenia. The identification of this possible pathophysiological process suggested a novel drug target for enhancing working memory function in schizophrenia that is currently under investigation.

Schematic summary diagram of the components of a disease process

Figure 1. Schematic summary of the components of a disease process. The cluster of clinical signs and symptoms (clinical syndrome) characteristic of a brain disorder, such as schizophrenia, is the result of some cause or set of causes (etiology). The interaction of these etiological factors induces the disease mechanisms (pathogenesis) which produce abnormalities in the brain (pathological entity) that alter its function (pathophysiology). The development of effective treatments or preventative measures requires the ability to interrupt or reverse the pathophysiological processes and pathogenetic mechanisms, respectively.
(Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience 6:312-324, 2005.)

David A. Lewis, MD / Department of Psychiatry / University of Pittsburgh
3811 O'Hara Street / Biomedical Science Tower W1650 / Pittsburgh, Pennyslvania 15213-2593 - Phone: (412) 624-3934 - Fax: (412) 624-9910