Phone: (412) 624-3934
Fax: (412) 624-9910
Email: lewisda@upmc.edu

Lab Website: http://cortex.psychiatry.pitt.edu/

M.D., Ohio State University

Research Interests

Dr. Lewis’ research activities focus on the neural circuitry of the prefrontal cortex and related brain regions, and the alterations of this circuitry in psychiatric disorders such as schizophrenia. The research strategy underlying these investigations involves five components. First, the normal functional architecture of the prefrontal cortex, including its connections with other cortical and subcortical regions, is examined using the macaque monkey as a model system for the human brain. Within these circuits, the expression and cellular localization of specific gene products, and how these change in an activity-dependent fashion, are investigated. In collaboration with Drs. Guillermo Gonzalez-Burgos and Leonid Krimer, the electrophysiological properties of intrinsic prefrontal cortical circuits are studied using an in vitro slice preparation.

The second component of this research strategy involves characterizing the postnatal development of prefrontal cortical circuitry. Special emphasis is placed on maturational events, such as synaptogenesis and synaptic pruning, which occur during early postnatal life and adolescence. The timing and specificity of these processes are examined for their possible contribution to the emergence and refinement of the types of cognitive abilities that are disturbed in schizophrenia.

Based on the results of these two lines of investigation, hypotheses are generated regarding the elements of neural circuitry that may be dysfunctional in schizophrenia. These hypotheses are then tested in postmortem human brain specimens from subjects with schizophrenia in collaboration with Dr. Takanori Hashimoto. These studies utilize a variety of molecular and anatomical approaches. In addition, the primate model system is used to assess the influence of psychotropic medications on the neural circuits of interest.

In the fourth type of study, mouse genetic models are used as “proof of concept” tests of cause-effect relationship. The goal of these studies is to define the pathogenetic and pathophysiological processes that give rise to the cognitive deficits of schizophrenia and to identify potential targets for therapeutic interventions.

Based on these findings, phase II clinical trials are conducted with novel compounds predicted to improve cognitive dysfunction in schizophrenia.

Recent Publications

• Eggan SM, Lewis DA: Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate cerebral cortex: A regional and laminar analysis. Cereb Cortex 17: 175-191. 2007.
• Lewis DA, Gonzalez-Burgos G: Pathophysiologically based treatment interventions in schizophrenia. Nature Medicine 12: 1016-1022, 2006.
• Maldonado-Avilés JG, Wu Q, Sampson AR, Lewis DA: Somal size of immunolabeled pyramidal cells in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 60: 226-234, 2006.
• González-Burgos G, Krimer LS, Povysheva NV, Barrionuevo G, Lewis DA: Functional properties of fast spiking interneurons and their synaptic connections with pyramidal cells in primate dorsolateral prefrontal cortex. J Neurophysiology 93: 942-953, 2005.
• Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nature Rev Neurosci 6: 312-324, 2005.
• Hashimoto T, Bergen SE, Nguyen, Q, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA: Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25: 372-383, 2005.