Glucocorticoid receptors recruit the CaMKIIα, BDNF–CREB pathways to mediate memory consolidation

Emotionally important events are well remembered. Although memories of emotional experiences are known to be mediated and modulated by the stress hormones glucocorticoids, little is known about the underlying molecular mechanisms. Here we show that the hippocampal glucocorticoid receptors critically engaged during the formation of long–term inhibitory avoidance memory in rats are coupled to the activation of CaMKIIα, TrkB, ERK, Akt, PLCγ and CREB, as well as a significant induction of Arc and synaptic GluA1. Most of these changes, which are initiated by a non–genomic effect of glucocorticoid receptors, are also downstream of the activation of brain–derived neurotrophic factor (BDNF). Hippocampal administration of BDNF, but not other neurotrophins, selectively rescues both the amnesia and the molecular impairments produced by glucocorticoid receptor inhibition. Hence, glucocorticoid receptors mediate long–term memory formation by recruiting the CaMKIIα–BDNF–CREB–dependent neural plasticity pathways.