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First published on January 12, 2007; DOI: 10.1124/mol.106.032490

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Received for publication November 8, 2006.
Revised January 11, 2007.
Accepted for publication January 12, 2007.

RGS4 modulates serotonin signaling in prefrontal cortex and links to serotonin dysfunction in a rat model of schizophrenia

Zhenglin Gu 1, Qian Jiang 1, Zhen Yan 1*

1 State Univ. of New York at Buffalo

* Address correspondence to: E-mail: zhenyan{at}buffalo.edu

Abstract

Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, it remains largely unknown about the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia. 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 (PCP), 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.


Key words: Serotonin, Glutamate, Ion channel regulation, RGS proteins


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