Pituitary adenylate cyclase‐activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHPin CA1 pyramidal neurons by activating multiple signaling pathways

Ruth D.T Taylor,Paola Pedarzani,Marisol Sampedro‐Castañeda,Michael Krause,Martin Stocker,Marita Grønning Madsen

doi:10.1002/hipo.22201

Abstract

The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP 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 sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP 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 sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP 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 sIAHP, 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.

Highlights

Action potentials in hippocampal pyramidal neurons are followed by an afterhyperpolarization (AHP) that has three kinetically distinct phases: fast, medium, and slow AHP
Given the structural similarity of pituitary adenylate cyclase activating peptide (PACAP) and VIP (Miyata et al, 1989; Miyata et al, 1990) and the fact that they share a subset of receptors (VPAC1 and VPAC2), coupled to the cyclic AMP (cAMP)-protein kinase A (PKA) pathway, we hypothesized that PACAP might suppress sIAHP in hippocampal pyramidal neurons
We found that PACAP-38 (500 nM) reduced the sIAHP amplitude (Figs. 1A,C) by 67% 6 5.9% (Fig. 1E, n 5 7) and the charge transfer by 77.3% 6 5.2% (Fig. 1E, n 5 7) in CA1 pyramidal neurons

Summary

Introduction

Action potentials in hippocampal pyramidal neurons are followed by an afterhyperpolarization (AHP) that has three kinetically distinct phases: fast (fAHP), medium (mAHP), and slow AHP (sAHP) (reviewed in Sah and Faber, 2002; Stocker et al, 2004). The sAHP is mediated by a slow calcium-dependent potassium current, sIAHP, that contributes to the late phase of spike frequency adaptation in hippocampal pyramidal neurons (Madison and Nicoll, 1982; Lancaster and Adams, 1986; Lancaster and Nicoll, 1987). Some neuropeptides expressed in interneurons and released in the hippocampal formation inhibit the sIAHP and reduce spike frequency adaptation in pyramidal neurons. These include the vasoactive intestinal peptide (VIP, Haas and Gahwiler, 1992), the corticotropin releasing factor (CRF, Aldenhoff et al, 1983) and the calcitonin gene-related peptide (CGRP, Haug and Storm, 2000), all exerting their inhibitory action on sIAHP via the cAMP-PKA pathway (Haug and Storm, 2000)

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