Probing Outside of the Synapse: Contribution of Extrasynaptic Glutamate to Neuropsychiatric Disorders

Glutamate represents the primary excitatory neurotransmitter and is involved in most aspects of brain functioning in the normal and diseased states. While synaptically released glutamate has been studied in great detail, a dearth of knowledge exists regarding the contribution of extrasynaptic glutamate release mechanisms, including cystine-glutamate antiporters (also referred to as system xc-), to pathological conditions involving glutamate dysfunction. The focus of my research is to determine whether extrasynaptic release mechanisms represent unrecognized targets in unmasking the etiology and treatment of psychiatric disorders.

We utilize a pathophysiological approach whereby the involvement of extrasynaptic release mechanisms in neuropsychiatric disorders is examined using preclinical models of schizophrenia and cocaine addiction. Currently, we are examining a) how cocaine and manipulations thought to model schizophrenia result in diminished glutamate release from system xc-, b) the impact of reduced system xc- activity on brain functioning in the normal and pathological states, and c) the potential for increased cystine-glutamate exchange following administration of cysteine prodrugs to reverse behaviors used to model aspects of these diseases as well as the symptoms of the disease in humans. To do this, the laboratory incorporates a number of molecular, neurochemical, and behavioral techniques to address these questions and collaborates with a number of external laboratories.

In addition to our research program, we have initiated a medication development program both within the laboratory at Marquette University and within a company recently cofounded by Drs. David Baker and John Mantsch (Promentis Pharmaceuticals, Inc.). Funding for our academic and commercial endeavors is provided by private investors as well as grants from the National Institute on Drug Abuse, National Institute of Mental Health, the State of Wisconsin, and the National Alliance for Research on Schizophrenia and Depression.

Selected Publications


BIOMEDICAL SCIENCES

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