Basic Developmental Neurobiology Research

One of the challenges facing researchers interested in understanding brain organization is to identify the cellular and molecular mechanisms regulating normal and pathological neuronal development. My research interests involve studies of the mouse cerebellum as a model system to analyze cellular and molecular developmental mechanisms at three levels of organization: 1) regulation of neuronal cell number, 2) mechanisms of afferent pattern formation, and 3) role of activity and neurotrophins in the regulation of Purkinje cell dendritic organization. A variety of quantitative anatomical, physiological, genetic, and molecular techniques are used in the laboratory to analyze cerebellar development in inbred and mutant mice, including naturally occurring, transgenic and knockout mouse mutants. For example, we are currently using Bcl-2 transgenic mice and Bax knockout mutants to study the mechanisms of cell death in the Lurcher mouse mutant. Lurcher is a gain-of-function mutation in the Grid2 receptor that causes the cell autonomous death of cerebellar Purkinje cells followed by the target-related death of granule cells and olivary neurons.

Preclinical Schizophrenia Research

There is continuing interest in schizophrenia as a developmental disorder: three of the major identified risk factors for schizophrenia (excess winter births, pregnancy and birth complications, and genetic linkage) may all influence the early development of the central nervous system. In collaborative studies with other researchers at the Maryland Psychiatric Research Center, we are developing animal models with behavioral deficits that are relevant for studies of the pathophysiology of schizophrenia and comorbidity for drug abuse. In other studies, we are analyzing the neuronal organization of the hippocampus, entorhinal cortex and cingulate cortex in postmortem brain tissue from schizophrenic patients and non-schizophrenic controls. The goal of this research is to identify structural or biochemical abnormalities in schizophrenic brains that will provide clues to the etiology of schizophrenia. 

Recent Studies

Research in this laboratory focuses on the widely accepted hypothesis that schizophrenia is a neurodevelopmental disorder. During the past year, major progress was made in the study of a protein called RGS4, which shows interesting expression patterns in the mammalian brain during the early postnatal period. The developmental expression of RGS4 is especially distinct in regions involved in the pathology of schizophrenia, such as the neocortex, the hippocampus, and the thalamus. The RGS4 protein is of particular interest in schizophrenia because it exerts direct influence on many receptors and neurotransmitter systems implicated in the disease, including certain dopamine, serotonin and glutamate receptors. Moreover, the gene encoding RGS4 has been identified as a susceptibility locus for schizophrenia. Work by H. Erdely, a graduate student (recently graduated), revealed not only that RGS4 is differentially expressed in discrete regions of the normal human brain but also showed a selective reduction in protein expression in the neocortex and other brain areas in individuals with schizophrenia. These results suggest that deficits in RGS4 function may contribute to the pathophysiology of the disease.

To further investigate the mechanisms underlying the changes in RGS4 expression seen in schizophrenia, the fate of RGS4 was analyzed in rats treated with phencyclidine (PCP; “angel dust”). PCP is a drug of abuse, which causes schizophrenia-like symptoms in normal individuals and worsens symptoms in individuals with schizophrenia. In addition to producing many of the “positive” symptoms of the disease, PCP also elicits ”negative” symptoms, including social withdrawal, and cognitive deficits such as impaired learning and memory. In a collaborative study with Drs. J. Koenig and P. Lee at the MPRC, RGS4 expression was found to be significantly altered in several brain regions in rats that had been treated with PCP for two weeks. These results indicate that discrete changes in brain RGS4 function in schizophrenia can be duplicated in the “PCP model” in animals. Ongoing experiments are designed to examine the functional consequences of these changes. In turn, these studies may lead to the conclusion that drugs capable of manipulating RGS4 in the brain hold promise in the treatment of schizophrenia.