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

Georgiev D, Yoshihara T, Kawabata R, Matsubara T, Tsubomoto M, Minabe Y, Lewis DA, Hashimoto T: Cortical gene expression after a conditional knockout of 67 kDa glutamic acid decarboxylase in parvalbumin neurons. Schizophr Bull 42:992-1002, 2016.
 
Volk DW, Sampson AR, Zhang Y, Edelson JR, Lewis DA: Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders. Psychol Med 46:2501-2512, 2016.
 
Datta D, Arion D, Roman KM, Volk DW, Lewis DA: Altered expression of ARP2/3 complex signaling pathway genes in prefrontal layer 3 pyramidal cells in schizophrenia. Am J Psychiatry, ePub August 13, 2016. 
 
Enwright JF, Sanapala S, Goflio A, Berry R, Fish KN, Lewis DA:  Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia.  Neuropsychopharmacology, 41:2206-14, 2016. 
 
Rocco BR, Lewis DA, Fish KN: Markedly lower glutamic acid decarboxylase 67 protein levels in a subset of boutons in schizophrenia. Biol Psychiatry, 79:1006-1015, 2016. 
 
Kimoto S, Glausier JR, Fish KN, Volk DW, Bazmi H, Arion D, Datta D, Lewis DA: Reciprocal alterations in regulator of G-protein signaling 4 and microRNA16 in schizophrenia. Schizophr Bull, ePub September 30, 2015. 
 
Chung W, Volk DW, Arion D, Zhang Y, Sampson AR, Lewis DA: Dysregulated ErbB4 splicing in schizophrenia: Selective effects on parvalbumin expression. Am J Psychiatry, 173:60-68, 2016. 
 
Rocco BR, Sweet RA, Lewis DA, Fish KN: GABA-synthesizing enzymes in calbindin and calretinin neurons in monkey prefrontal cortex. Cereb Cortex, ePub March 30, 2015. 
 

 

Volk DW, Chitrapu A, Edelson JR, Roman KM, Moroco AE, Lewis DA: Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry, 172:1112-1121, 2015.