Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sI(AHP) in CA1 pyramidal neurons by activating multiple signaling pathways

The slow afterhyperpolarizing current (sI(AHP)) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sI(AHP) is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sI(AHP) and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sI(AHP), resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sI(AHP) by PACAP is mediated by PAC(1) and VPAC(1) receptors. Inhibition of PKA reduced the effect of PACAP on sI(AHP), suggesting that PACAP exerts part of its inhibitory effect on sI(AHP) by increasing cAMP and activating PKA. The suppression of sI(AHP) by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sI(AHP). Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sI(AHP) in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sI(AHP) through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sI(AHP), underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.