Calcium/Calmodulin-Stimulatable Adenylyl cyclases are required for the potentiating effect of acute glucocorticoid exposure in the hippocampal synapse release_kclid6a3cfeubhwulfayh5qguu

by Chinedu T Udeh-Momoh, Thomas Piers, Jee-Hyun Yi, Eleanor Waite, Garry Whitehead, Daniel Whitcomb, Stafford L Lightman, Kwangwook K Cho, Becky Conway-Campbell

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<jats:title>Abstract</jats:title> 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. The stress hormone glucocorticoid, exerts effects on synaptic plasticity through functional modification of these receptors. In this study, we have investigated the mechanisms underlying synaptic potentiation during acute stress and glucocorticoid treatment. We report that stress-induced glucocorticoid increase augments the postsynaptic localisation and phosphorylation of calcium permeable AMPAR, GluA1 and enhances long-term potentiation (LTP) observed 60 minutes following high frequency stimulation. These effects could be reproduced in adrenalectomized rats by the administration of a stress-equivalent dose of corticosterone. The observed response was blocked by the glucocorticoid receptor (GR) antagonist RU-486, thus potentially mediated by the GR. Glucocorticoid treatment further increased expression of hippocampal adenylyl cyclases (ACs), AC1 and AC8, implicating this class of enzymes as mediators of hyper-glucocorticoid effect on synaptic plasticity. In support of this, selective pharmacological AC inhibition with SQ22536 ablated the glucocorticoid modulation of AMPA-dependent neuronal plasticity and enhancement of LTP. These data support a key role for calcium/calmodulin-sensitive adenylyl cyclase enzymes in facilitating the modulatory actions of glucocorticoid hormones on a substrate for cellular mechanism of learning and memory, via AMPA receptor activation.
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