Ca2+/calmodulin-stimulated Adenylyl Cyclases are Required for the Potentiating Effect of Glucocorticoid Exposure in the Rat Hippocampal Synapse

Experience-dependent synaptic plasticity is important for learning and memory and regulated by the functions of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Glucocorticoids have been shown to augment synaptic potentiation processes during stress, however the underlying mechanisms have not been fully described. In this study, we have investigated the role of the Adenylyl cyclases in glucocorticoid enhancement of synaptic potentiation. We report that stress-induced glucocorticoid secretion augments phosphorylation and postsynaptic localisation of GluA1. These effects were reproduced in adrenalectomised rats treated with a stress-equivalent dose of corticosterone; and blocked by pre-treatment with the glucocorticoid receptor (GR) antagonist RU-486. Selective pharmacological inhibition of adenylyl cyclase activity with SQ22536 ablated the glucocorticoid-induced increase in phosphorylated GluA1, and reversed glucocorticoid-dependent LTP enhancement. Glucocorticoid exposure also induced induce a rapid increase in translation of hippocampal adenylyl cyclases 1 and 8, indicating a further potential role in mediating the longer-term consequences of stress. These data support a key role for adenylyl cyclases in facilitating the modulatory actions of glucocorticoid hormones on AMPA receptor regulation of learning and memory; initially as an acute mediator of the hormonally induced stress increase in LTP, then potentially in mediating adaptive changes for subsequent stress effects.