David A. Lewis, M.D.

Research Summary:

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.

Selected Publications:

Georgiev G, Arion D, Enwright JF, Kikuchi M, Minabe Y, Corradi JP, Lewis DA, Hashimoto T: Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia. Am J Psychiatry 171:62-71, 2014. 

Glausier JR, Fish KN, Lewis DA: Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry 19:30-36, 2014. 

Cho RY, Walker CP, Polizzotto NR, Wozny TA, Fissell C, Chen CA, Lewis DA: Development of sensory gamma oscillations and cross-frequency coupling from childhood to early adulthood. Cerebral Cortex, ePub December 10, 2013. 

Povysheva NV, Zaitsev AV, Gonzalez-Burgos G, Lewis DA: Electrophysiological heterogeneity of fast-spiking interneurons: Chandelier versus basket cells. PLoS One 8:e70553, 2013. 

Gonzalez-Burgos G and Lewis DA: NMDA receptor hypofunction, parvalbumin-positive neurons and cortical gamma oscillations in schizophrenia. Schizophr Bull 38:950-957, 2012. 

Glausier JR, Lewis DA. Dendritic spine pathology in schizophrenia. Neurosci, in press. 

Lewis DA, Curley AA, Glausier JR, Volk DW: Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35(1):57-67, 2012. 

Curley AA, Lewis DA: Cortical basket cell dysfunction in schizophrenia. J Physiol 590(Pt 4):715-724, 2012. 

Hoftman GD, Lewis DA: Postnatal developmental trajectories of neural circuits in the primate prefrontal cortex: identifying sensitive periods for vulnerability to schizophrenia. Schizophr Bull37(3):493-503, 2011. 

Lewis DA: The chandelier neuron in schizophrenia. Dev Neurobiol 71:118-127, 2011. 

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

Gonzalez-Burgos G, Lewis DA: GABA neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull 34: 944-961, 2008. 

Lewis DA, Gonzalez-Burgos G: Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology Rev 33: 141-165, 2008. 

Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312-324, 2005.