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Liu, W. et al. Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc. Natl. Acad. Sci. USA 103, 18338-18343

Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2006; 103(48):18338-43. DOI: 10.1073/pnas.0604560103
Source: PubMed

ABSTRACT The noradrenergic system in the prefrontal 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 alpha1- and alpha2-adrenergic receptors (alpha1-ARs, alpha2-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 alpha1-AR or alpha2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The alpha1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca(2+) pathway, whereas the alpha2-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 alpha1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting alpha2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on alpha1-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 alpha2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of alpha1-ARs or alpha2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of alpha1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of alpha2-ARs is modified by RGS4 independent of spinophilin.

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    • "In fact, NE has a variety of effects at alpha-as well as beta-receptors in central neurons. Previous studies indicate that NE at 10–20 lM range consistently decreases alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-induced current (Dinh et al., 2009), AMPA–EPSC (Law-Tho et al., 1993; Kobayashi, 2007; Kobayashi et al., 2009), or N-methyl- D-aspartate (NMDA)–EPSC (Liu et al., 2006) via either postsynaptic activation of alpha-1 receptor in the PFC or presynaptic alpha-2 receptor in amygdala (Delaney et al., 2007), or even postsynaptic alpha-2 receptor in PFC (Ji et al., 2008b). Whatever the receptor-specificity and pre-or postsynaptic action, the consistent finding of a depressive effect of NE on excitatory synaptic transmission is contradictory to the insignificant effect of NE in P–P monosynaptic connections as observed in the current study. "
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    ABSTRACT: The noradrenergic system of the brain is thought to facilitate neuronal processes that promote behavioral activation, alertness, and attention. It is known that norepinephrine (NE) can be significantly elevated in the prefrontal cortex under normal conditions such as arousal and attention, and following administration of psychostimulants and various other drugs prescribed for psychiatric disorders. However, how NE modulates neuronal activity and synapses in the local prefrontal circuitry remains elusive. In this study, we characterized the actions of NE on individual monosynaptic connections among layer V pyramidal neurons (P) and fast-spiking (FS) GABAergic interneurons in the juvenile (postnatal days 20-23) rat prefrontal local circuitry. We found that NE selectively depresses excitatory synaptic transmission in P-FS connections but has no detectable effect on the excitatory synapses in P-P connections and the inhibitory synapses in FS-P connections. NE apparently exerts distinctly different modulatory actions on identified synapses that target GABAergic interneurons but has no effect on those in the pyramidal neurons in this specific developmental period. These results indicate that, depending on the postsynaptic targets, the effects of NE in prefrontal cortex are synapse-specific, at least in the juvenile animals.
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    • "We initially defined a system of interest based on previous CeA alcohol studies including GABA A (Bajo et al., 2008; Nie et al., 2004), NMDA (McCool et al., 2010; Obara et al., 2009; Roberto et al., 2004, 2006), GPCR subunits including Grm5, Crhr1, Oprm1, Cckbr, Gnb4, and genes related to GPCR function like Ace, Ace2, Agtrap, and Ren (Cruz et al., 2012; Kitanaka et al., 2008). This list was expanded to include associated regulatory elements including Rgs (Ho et al., 2010; Liu et al., 2006) and receptor trafficking proteins (Obara et al., 2009), downstream signaling components (Bajo et al., 2008; Sanna et al., 2002), TFs (Pandey, 2004; Radwanska et al., 2008; Vilpoux et al., 2009), and inducible targets (McBride et al., 2010) as shown in a schematic in Fig. 2 and in detail in Fig. 4A. The result is a focused and highly relevant gene set that can be examined over time during withdrawal. "
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    • "Predominantly, we chose genes for proteins known to be affected by alcohol consumption, alcohol withdrawal, or anxiety. This included individual GABA A (Breese et al. 2006), N-Methyl-D-aspartic acid (NMDA) (Roberto et al. 2006, Nagy 2008), and G-protein coupled receptor (GPCR) subunits and downstream signaling components (Sanna et al. 2002, Liu et al. 2006, Lomazzi et al. 2008), as shown in a simplified schematic in Fig. 2. The selected set also included other targets identified by previous gene expression studies (Hashimoto et al. 2011, Covarrubias and Khan et al. 2005, Sommer et al. 2006, Tabakoff et al. 2009, Arlinde et al. 2004). Additionally, to focus on the cardiovascular regulatory role of the DVC, we included the genes encoding members of the angiotensin II type I receptor signaling (AT1R) pathway. "
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