I received my medical degree from The Ohio State University, completed residencies in internal medicine and in psychiatry at the University of Iowa, and received my research training at the Research Institute of the Scripps Clinic.

“Although schizophrenia is a very complex disorder, we are beginning to understand aspects of the pathology and pathophysiology of this illness, and this understanding offers hope for new treatments that are based on knowledge of the underlying disease process.”

My research activities focus on the neural circuitry of the prefrontal cortex and related brain regions, and the alterations of this circuitry in schizophrenia. The research strategy underlying these investigations involves several 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. The electrophysiological properties of intrinsic prefrontal cortical circuits are studied using an in vitro slice preparation.

Second, the postnatal development of prefrontal cortical circuitry is characterized, with special emphasis 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.

Third, based on the results of these 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.

Fourth, the primate model system is used to assess the influence of psychotropic medications on the neural circuits of interest, and mouse genetic models are used as "proof of concept" tests of the cause-effect relationships between the alterations observed in the disease state. The goal of these studies is to define the pathogenetic mechanisms and pathophysiological processes that give rise to the cognitive deficits of schizophrenia. Finally, these findings are used to identify potential targets for novel therapeutic interventions that are examined in Phase II clinical trials.

Our goal was to determine if the density of dendritic spines, markers, and mediators of excitatory inputs to cortical pyramidal cells were altered in the prefrontal cortex of individuals with schizophrenia, and if so, whether these alterations were regionally, laminarly, and diagnostically specific. We found a significant (~20%) lower spine density on deep layer 3 pyramidal neurons in the prefrontal cortex of individuals with schizophrenia relative to both control subjects and subjects with other psychiatric disorders. This decrement was larger than that found in superficial layer 3 or in the primary visual cortex.

We have further determined that these effects are more marked in deep layer 3 than in layers 5 or 6, and that other markers of pyramidal cell morphology are more altered for deep layer 3 pyramidal neurons than for other cell types. Because of this laminar specificity, we have sought to determine whether reductions in specific sources of excitatory inputs could account for these changes. Most recently, we have been attempting to identify the molecular mechanisms that may underlie the spine alterations. These findings have been reviewed in a just-published paper in Neuropsychopharmacology Reviews.

Our studies on alterations in GABA neurotransmission in subsets of inhibitory neurons have contributed to hypotheses regarding how alterations in cortical network oscillations could lead to the information processing impairments in schizophrenia and have lead to a clinical trial of a novel drug.

Although schizophrenia is a very complex disorder, we are beginning to understand aspects of the pathology and pathophysiology of this illness, and this understanding offers hope for new treatments that are based on knowledge of the underlying disease process.