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

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Signaling

Background:

• Long-term depression (LTD) in the hippocampus is crucial for memory formation.
• cAMP-dependent protein kinase A (PKA) is a known mediator of hippocampal LTD.
• The role of exchange protein directly activated by cyclic AMP (Epac) in LTD is less understood.

Purpose of the Study:

• To investigate the involvement of Epac in hippocampal LTD.
• To elucidate the signaling pathways and molecular mechanisms underlying Epac-induced LTD.

Main Methods:

• Pharmacological activation of Epac using 8-(4-chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT).
• Assessment of synaptic transmission and paired-pulse facilitation in the CA1 region.
• Inhibition studies using brefeldin-A (BFA), geranylgeranyltransferase inhibitor (GGTI), SB203580, a GluR2 mimetic peptide, thapsigargin, lactacystin, anisomycin, and actinomycin-D.
• Investigation of pituitary adenylate cyclase activating polypeptide (PACAP) receptor involvement.

Main Results:

• Pharmacological activation of Epac induced LTD in the CA1 region, independent of presynaptic mechanisms.
• Epac-LTD was dependent on Epac signaling, postsynaptic mechanisms involving PDZ protein interactions, intracellular calcium mobilization, proteasome activity, and mRNA translation.
• Pituitary adenylate cyclase activating polypeptide (PACAP) stimulation induced an LTD occluded by Epac-LTD, suggesting a link between PACAP receptors and Epac signaling.

Conclusions:

• Epac mediates a novel form of hippocampal LTD.
• This Epac-dependent LTD involves specific postsynaptic molecular players and intracellular processes.
• Epac-LTD may be activated by PACAP receptor stimulation, highlighting a new pathway for synaptic plasticity regulation.