Glutamate Receptor Modulation Is Restricted to Synaptic Microdomains

A diverse array of neuromodulators governs cellular function in the prefrontal cortex (PFC) via the activation of G-protein-coupled receptors (GPCRs). However, these functionally diverse signals are carried and amplified by a relatively small assortment of intracellular second messengers. Here, we examine whether two distinct Gαi-coupled neuromodulators (norepinephrine and GABA) act as redundant regulators of glutamatergic synaptic transmission. Our results reveal that, within single dendritic spines of layer 5 pyramidal neurons, alpha-2 adrenergic receptors (α2Rs) selectively inhibit excitatory transmission mediated by AMPA-type glutamate receptors, while type B GABA receptors (GABABRs) inhibit NMDA-type receptors. We show that both modulators act via the downregulation of cAMP and PKA. However, by restricting the lifetime of active Gαi, RGS4 promotes the independent control of these two distinct target proteins. Our findings highlight a mechanism by which neuromodulatory microdomains can be established in subcellular compartments such as dendritic spines. [Display omitted] •Adrenergic α2Rs reduce AMPAR currents while GABABRs reduce NMDAR Ca2+ influx•Adrenergic and GABAergic control of glutamate receptors occurs via inhibition of PKA•Modulatory microdomains are established by co-localization and the actions of RGS4 Lur and Higley demonstrate that norepinephrine and GABA differentially regulate AMPAR-mediated currents and NMDAR-mediated Ca2+ influx, respectively. These distinct actions are driven by downregulation of PKA signaling and occur due to the existence of functional microdomains that are maintained by receptor co-localization and the actions of RGS4.