Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin

The noradrenergic system in the pref rontal cortex (PFC) is involved in many physiological and psychological processes, including working memory and mood control. To understand the functions of the noradrenergic system, we examined the regulation of NMDA receptors (NMDARs), key players in cognition and emotion, by alpha 1- and alpha 2-adrenergic receptors (alpha 1-ARs, alpha 2-ARs) in PFC pyramidal neurons. Applying norepinephrine or a norepinephrine transporter inhibitor reduced the amplitude but not paired-pulse ratio of NMDAR-mediated excitatory postsynaptic currents (EPSC) in PFC slices. Specific alpha 1-AR or alpha 2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The alpha 1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca2+ pathway, whereas the a2-AR effect depended on protein kinase A and the microtubule-based transport of NMDARs that is regulated by ERK signaling. Furthermore, two members of the RGS family, RGS2 and RGS4, were found to down-regulate the effect of alpha 1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting a2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on alpha 1-AR signaling were lost in mutant mice lacking spinophilin, which binds several RGS members and G protein-coupled receptors, whereas the effect of RGS4 on a2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of alpha 1-ARs or a2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of alpha 1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of a2-ARs is modified by RGS4 independent of spinophilin.