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Molecular Pharmacology Fast Forward
First published on January 12, 2007; DOI: 10.1124/mol.106.032490

0026-895X/07/7104-1030-1039$20.00
Mol Pharmacol 71:1030-1039, 2007

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RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Zhenglin Gu, Qian Jiang, and Zhen Yan

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York

Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT1A receptors or dopamine D4 receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT1A effect. In contrast, the D4 regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT1A regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.

Received November 8, 2006; accepted January 12, 2007

Address correspondence to: Zhen Yan, Department of Physiology and Biophysics, State University of New York at Buffalo, 124 Sherman Hall, Buffalo NY, 14214. E-mail: zhenyan{at}buffalo.edu.




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