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

Authors

  • Ruth D.T. Taylor,

    1. Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Current affiliation:
    1. MRC Center for Developmental Neurobiology, King's College London, London, UK
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    • R. D. T. Taylor and M. G. Madsen contributed equally to this work.

  • Marita Grønning Madsen,

    1. Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    Current affiliation:
    1. Lund Stem Cell Center, Lund University Hospital, SE-221 84 Lund, Sweden
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    • R. D. T. Taylor and M. G. Madsen contributed equally to this work.

  • Michael Krause,

    1. Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany
    Current affiliation:
    1. Gilead Sciences, Fremont, California 94555, USA
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  • Marisol Sampedro-Castañeda,

    1. Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
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  • Martin Stocker,

    Corresponding author
    1. Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    • Correspondence to: Martin Stocker, Research Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. E-mail: m.stocker@ucl.ac.uk or Paola Pedarzani, Research Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. E-mail: p.pedarzani@ucl.ac.uk

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  • Paola Pedarzani

    Corresponding author
    1. Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom
    • Correspondence to: Martin Stocker, Research Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. E-mail: m.stocker@ucl.ac.uk or Paola Pedarzani, Research Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. E-mail: p.pedarzani@ucl.ac.uk

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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.

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