Epac mediates PACAP‐dependent long‐term depression in the hippocampus

Abstract

Extensive work has shown that activation of the cAMP-dependent protein kinase A (PKA) is crucial for long-term depression (LTD) of synaptic transmission in the hippocampus, a phenomenon that is thought to be involved in memory formation. Here we studied the role of an alternative target of cAMP, the exchange protein factor directly activated by cyclic AMP (Epac). We show that pharmacological activation of Epac by the selective agonist 8-(4-chlorophenylthio)-2 -O-methyl-cAMP (8-pCPT) induces LTD in the CA1 region. Paired-pulse facilitation of synaptic responses remained unchanged after induction of this LTD, suggesting that it depended on postsynaptic mechanisms. The 8-pCPT-induced LTD was blocked by the Epac signalling inhibitor brefeldin-A (BFA), Rap-1 antagonist geranylgeranyltransferase inhibitor (GGTI) and p38 mitogen activated protein kinase (P38-MAPK) inhibitor SB203580. This indicated a direct involvement of Epac in this form of LTD. As for other forms of LTD, a mimetic peptide of the PSD-95/Disc-large/ZO-1 homology (PDZ) ligand motif of the AMPA receptor subunit GluR2 blocked the Epac-LTD, suggesting involvement of PDZ protein interaction. The Epac-LTD also depended on mobilization of intracellular Ca2+ , proteasome activity and mRNA translation, but not transcription, as it was inhibited by thapsigargin, lactacystin and anisomycin, but not actinomycin-D, respectively. Finally, we found that the pituitary adenylate cyclase activating polypeptide (PACAP) can induce an LTD that was mutually occluded by the Epac-LTD and blocked by BFA or SB203580, suggesting that the Epac-LTD could be mobilized by stimulation of PACAP receptors. Altogether these results provided evidence for a new form of hippocampal LTD.

A Model for Sealing Plasmalemmal Damage in Neurons and Other Eukaryotic Cells

“…Epac increases membrane fusion by activating Sec1/Munc13 (Kwan et al, 2007) or SNARE proteins (Sedej et al, 2005). Inhibition of trans-Golgi traffic using the bacterial toxin brefeldin A decreases the influence of Epac on synaptic transmission, suggesting that Epac isoforms activate Rab3A exocytosis in both synaptic and Golgi trafficking pathways (Ster et al, 2009). That is, Epac pathways likely activate proteins in the PKA pathway (e.g., Rab3A, mUNC proteins, SNAREs) (Hochbaum et al, 2008), but also may activate parallel (redundant) Ca 2ϩ -dependent pathways important for plasmalemmal sealing (Fig.…”

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

“…An Epac-null mutation impairs long-term potentiation (LTP) that is paralleled with the severe deficits in spatial learning and social interactions (Yang et al, 2012). Epac is thought to be a key mediator in the effects of PACAP (Ster et al, 2009), a peptide that has been recently implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and fear memory formation (Ressler et al, 2011). Thus, NPY may modulate a variety of behaviors, including conditioned fear (Gutman et al, 2008) and human stress reactivity (Mickey et al, 2011;Witt et al, 2011) via Epac pathways and serve as a critical element in the pathophysiology of depression, PTSD, and other neuropsychiatric disorders.…”

The neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10/N-Cadherin signaling pathway

“…By contrast, another study showed that the application of PACAP38 enhanced AMPA-evoked currents (Michel et al, 2006). PACAP38 has been also shown to induce a form of long-term depression (LTD) in hippocampal neurons that requires interaction of AMPA receptor subunits with scaffolding proteins (Kondo et al 1997;Roberto et al 2001;Ster et al, 2009), thus validating its role in learning and memory. This has been further confirmed by the use of transgenic animals (Yang et al, 2010).…”