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

Abstract

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.

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

“…This may reflect an actual difference between cultures and in vivo systems, or simply that more sensitive techniques would be needed to address this specific question in vivo. This theory, however, is supported by recent work 58 describing crosstalk between GR and TrkB signalling activated-pathways, including activation of PLCg during aversive memory formation in the rat. The authors were also unable to demonstrate any direct interaction between the two receptors in vivo 58 .…”

“…This theory, however, is supported by recent work 58 describing crosstalk between GR and TrkB signalling activated-pathways, including activation of PLCg during aversive memory formation in the rat. The authors were also unable to demonstrate any direct interaction between the two receptors in vivo 58 . In addition, we have also found a significant decrease of projecting CCK-YFP þ fibres associated with CRH neurons in the PVN of mutant mice.…”

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…In addition, GR-mediated transcriptional activation is modulated both positively and negatively by phosphorylation (Ismaili & Garabedian 2004) of kinases and phosphatases. Although the activity of the GR is often thought in terms of direct gene transactivation, considerable crosstalk also occurs between the GR and a cohort of molecules to mediate their function as transcriptional factors, including octamer transcription factors, OCT1 and OCT2, cyclic adenosine monophosphate response element-binding protein and signal transducers and activators of transcription 5 (Engblom et al 2007, Chen et al 2012, Ratman et al 2013. Competition for limiting transcription co-activators is an important determinant of the fate of the crosstalk between the GR and other transcription factors.…”

Challenging Oneself Intermittently to Improve Health

“…BDNF plays critical roles in learning and memory (Gomez-Pinilla and Hillman, 2013), and may mediate the improved cognitive function that is observed in runners compared to non-runner rats and mice (Marosi and Mattson, 2014). The mechanisms by which running 'strengthens' synapses involves binding of BDNF to a receptor called TrkB resulting in the activation of the kinases Akt and ERK (extracellular signal regulated kinase), and the downstream transcription factors cyclic AMP response element binding protein (CREB) and NF-kB (Kuipers and Bramham, 2006;Gavalda et al, 2009;Chen et al, 2012). The hippocampus, a brain region critical for learning and memory, contains stem cells that can divide and can differentiate into new neurons or glial cells.…”