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

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-HT _1A 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-HT_1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT_1A effect. In contrast, the D₄ regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT_1A 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.