G protein-coupled receptors can regulate diverse physiological functions through the activation of different G proteins. The activities of particular Gαs protein-coupled receptors in the hippocampus, such as dopamine and norepinephrine receptors, play crucial roles in neural circuit regulation and contribute to memory formation and consolidation. However, the ubiquitous distribution of Gαs protein-coupled receptors in the brain has made it difficult to precisely identify their specific roles in the hippocampus with high spatial resolution. Here, the pharmacogenetic technology, “Designer Receptors Exclusively Activated by Designer Drugs” (DREADD) was applied to study the function of Gαs protein-coupled receptors in a spatially restricted manner. The results show that the specific activat...[ Read more ]

G protein-coupled receptors can regulate diverse physiological functions through the activation of different G proteins. The activities of particular Gαs protein-coupled receptors in the hippocampus, such as dopamine and norepinephrine receptors, play crucial roles in neural circuit regulation and contribute to memory formation and consolidation. However, the ubiquitous distribution of Gαs protein-coupled receptors in the brain has made it difficult to precisely identify their specific roles in the hippocampus with high spatial resolution. Here, the pharmacogenetic technology, “Designer Receptors Exclusively Activated by Designer Drugs” (DREADD) was applied to study the function of Gαs protein-coupled receptors in a spatially restricted manner. The results show that the specific activation of Gαs protein-coupled receptors in the postsynaptic region of the mouse hippocampal CA1 region enhances long-term potentiation (LTP), which is likely the cellular basis of learning and memory. Moreover, the action of Gαs protein-coupled receptors is mediated through the regulation of synaptic AMPA receptor, as evidenced by increased AMPA receptor subunit GluA1 phosphorylation at Ser845. Furthermore, activation of Gαs protein-coupled receptors significantly enhanced hippocampus-dependent contextual memory. Together, these findings revealed that Gαs protein-coupled receptors play a positive role in regulating synaptic plasticity and memory in hippocampus.