Integrated Approaches to Develop Improved Schizophrenia Therapies

Integrated Approaches to Develop Improved Schizophrenia Therapies

Posted: March 5, 2014

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From The Quarterly, Winter 2014

The symptoms of schizophrenia have been managed for the past half-century through the use of antipsychotics, but the medications that currently exist are not adequate to treat all the symptoms of this complex disease and they also have serious side effects. All clinically effective antipsychotics block the actions of the neurotransmitter dopamine by interacting with dopamine D2 receptors, which are members of a large family of proteins, called G protein-coupled receptors (GPCR). Activation of a GPCR by a neurotransmitter generates a cellular signal and response that is rapid and robust and must be carefully turned off in a process called de-sensitization.

In his presentation, Dr. Caron described research in his laboratory that has shown that these GPCR de-sensitization mechanisms carry out previously unrecognized cellular signaling events. Also, GPCR can be activated to one pathway and block another, or vice versa, giving rise to the notion of functional selectivity. The lab’s further work with genetically engineered mice has revealed that antipsychotics can target the molecular de-sensitization machinery of dopamine D2 receptors in a preferential fashion. This had led Dr. Caron to the idea that it might be possible to separate the beneficial and negative effects of antipsychotics on the basis of functional selectivity.

To validate the concept of GPCR signaling as potentially relevant to the development of schizophrenia and the actions of antipsychotics, the Caron team has shown that genetic manipulations of components of this signaling pathway recapitulate schizophrenia-like symptoms in mouse models. Dr. Caron and colleagues are now leveraging the concept of GPCR functional selectivity to develop novel, more efficacious antipsychotics. 

A graduate of Laval University, in Quebec City, Dr. Caron earned his Ph.D. in biochemistry at the University of Miami. After a postdoctoral fellowship at Duke he first returned to Laval as an Assistant Professor in the Department of Physiology and then joined the Duke faculty, where he was also a Howard Hughes Medical Institute Senior Associate and Investigator.

Marc G. Caron, Ph.D.

James B. Duke Professor of Cell Biology

and Professor of Medicine and of Neurobiology

Duke University Medical Center

2013 Lieber Prize for Outstanding Achievement in Schizophrenia Research

Brain & Behavior Research Foundation Scientific Council Member

2005 NARSAD Distinguished Investigator Grant