David A. Lewis, MD

UPMC Professor and Chair, Psychiatry, Neuroscience, Translational Neuroscience

Contact

W1653 Biomedical Science Tower
412-624-3934
F: 412-624-9910
lewisda@upmc.edu
Website >

Education

MD, Ohio State University (1979)

Focus

Functional architecture of the prefrontal cortex and schizophrenia.

Research Summary

Dr. Lewis is the UPMC Professor in Translational Neuroscience

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 Dr. Guillermo Gonzalez-Burgos, 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. The effects on prefrontal cortical circuitry of chronic exposure to cannabis during adolescence, a risk factor for schizophrenia, are examined at the molecular, circuitry and behavioral levels.

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. 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.

Publications

Beneyto M, Abbott A, Hashimoto T, Lewis DA: Lamina-specific alterations in cortical GABAA receptor subunit expression in schizophrenia. Cereb Cortex, ePub September 15, 2010.

Arion, D. and Lewis, D.A. Altered expression of regulators of the cortical choloride transporters NKCC1 and KCC2 in schizophrenia. Arch Gen Psychiatry, ePub September 6, 2010.

Lewis, D.A. and Sweet, R.A. Schizophrenia from a neural circuitry perspective: Advancing toward rational pharmacological therapies. J Clin Invest 119: 706-716, 2009.

Maldonado-Avil_s, J.G., Curley, A.A., Hashimoto, T., Morrow, A.L., Ramsey, A.J., O'Donnell, P., Volk, D.W. and Lewis, D.A. Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia. Am J Psychiatry 166: 450-459, 2009.

Lewis, D.A., Cho, R.Y., Carter, C.S., Eklund, K., Forster, S., Kelly, M.A. and Montrose, D. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry, 165: 1585-1593, 2008.

Gonzalez-Burgos, G., Kr_ner, S., Zaitsev, A., Povysheva, N., Krimer, L., Barrionuevo, G. and Lewis, D.A. Functional maturation of excitatory synapses in layer 3 pyramidal neurons during postnatal development of the primate prefrontal cortex. Cereb Cortex 18: 626-637, 2008.

Lewis, D.A. and Gonzalez-Burgos, G. Pathophysiologically based treatment interventions in schizophrenia. Nature Medicine 12:1016-1022, 2006.

Lewis, D.A., Hashimoto, T. and Volk, D.W. Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience 6:312-324, 2005.