Epac signaling is required for hippocampus-dependent memory retrieval

Abstract

Previously we uncovered a critical role for norepinephrine and ␤1-adrenergic signaling in hippocampus-dependent memory retrieval. Because the ␤1 receptor couples to Gs, we examine here whether cAMP is also required for contextual memory retrieval. Using pharmacologic and genetic approaches to manipulate cAMP and downstream signaling, we demonstrate that cAMP and two of its targets, protein kinase A (PKA) and exchange protein activated by cAMP (Epac), are both required for retrieval. These findings demonstrate that cAMP signaling through Epac (as well as PKA) plays an essential role in cognition.norepinephrine ͉ protein kinase A ͉ context ͉ ␤-adrenergic ͉ cyclic AMP

Inhibition of β-Adrenergic Receptors Induces a Persistent Deficit in Retrieval of a Cocaine-Associated Memory Providing Protection against Reinstatement

“…Direct stimulation of locus coeruleus neurons facilitates memory retrieval (Devauges and Sara, 1991;Sara and Devauges, 1988), supporting the notion that stimulus-evoked norepinephrine release initiates memory retrieval. As a result, disruption of noradrenergic signaling by propranolol prevents retrieval (Murchison et al, 2004;Ouyang et al, 2008; present findings) and may render drugassociated stimuli less salient. This effect could be due to a deficit in attention, such that rats are unaware of the salience previously attributed to the drug-associated chamber.…”

“…Our finding that propranolol disrupts the retrieval of a cocaine-associated memory agrees with previous investigations. b-Adrenergic signaling has a pivotal role in retrieval of context-conditioned fear (Murchison et al, 2004;Ouyang et al, 2008) and the expression of cue-conditioned fear (Rodriguez-Romaguera et al, 2009), both of which are disrupted by propranolol. Propranolol prevents stressinduced reinstatement of drug seeking (Mantsch et al, 2010) and context-induced reinstatement of cue-conditioned fear (Morris et al, 2005), which could be attributed to memory retrieval blockade.…”

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

“…There is increasing evidence that Epac is a mediator of cAMP-dependent changes in hippocampal synaptic plasticity (Gelinas et al, 2008;Whitaker and Wei, 2009;Woolfrey et al, 2009) and memory retrieval (Ostroveanu et al, 2010;Ouyang et al, 2008). Epac also appears to be implicated in the regulation of neurotransmitter release (Gekel and Neher, 2008;Kaneko and Takahashi, 2004) as well as synaptic and spine modulation that are critical for neuronal plasticity (Woolfrey et al, 2009).…”

Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling

“…However, there is evidence that b 2 receptors can also signal through G i/o (Xiao et al 1995;Daaka et al 1997;Devic et al 2001). Because cAMP signaling is necessary and sufficient for contextual memory retrieval mediated by NE and b 1 receptors (Ouyang et al 2008), we asked whether b 2 signaling might oppose b 1 /G s signaling in retrieval by activating G i/o .…”

“…cAMP antagonists impair retrieval when infused into the DH shortly before testing contextual fear, and DH infusion of cAMP agonists rescues retrieval in genetargeted mice lacking NE (Ouyang et al 2008). Further, activation of at least two targets of cAMP signaling, protein kinase A (PKA) and the exchange protein activated by cAMP (Epac), is also required for hippocampus-dependent memory retrieval.…”