A subnanomolar concentration of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) pre-synaptically modulates glutamatergic transmission in the rat hippocampus acting through acetylcholine.
The neuropeptide PACAP modulates synaptic transmission in the hippocampus exerting multiple effects through different receptor subtypes: the underlying mechanisms have not yet been completely elucidated. The neurotransmitter acetylcholine (ACh) also exerts a well-documented modulation of hippocampal synaptic transmission and plasticity. Since PACAP was shown to stimulate ACh release in the hippocampus, we tested whether PACAP acting through ACh might indirectly modulate glutamate-mediated synaptic transmission at a pre- and/or at a post-synaptic level. Using patch clamp on rat hippocampal slices, we tested PACAP effects on stimulation-evoked AMPA receptor-mediated excitatory post-synaptic currents (EPSCsAMPA) in the CA3-CA1 synapse and on spontaneous miniature EPSCs (mEPSCs) in CA1 pyramidal neurons. A subnanomolar dose of PACAP (0.5nM) decreased EPSCsAMPAamplitude, enhanced EPSC paired-pulse facilitation (PPF) and reduced mEPSC frequency, indicating a pre-synaptic decrease of glutamate release probability: these effects were abolished by simultaneous blockade of muscarinic and nicotinic ACh receptors, indicating the involvement of endogenous ACh. The effect of subnanomolar PACAP was abolished by a PAC1 receptor antagonist but not by a VPAC receptor blocker. At a higher concentration (10nM), PACAP inhibited EPSCsAMPA: this effect persisted in the presence of ACh receptor antagonists and did not involve any change in PPF or in mEPSC frequency, thus was not mediated by ACh and was exerted post- synaptically on CA1 pyramidal neurons. We suggest that a high-affinity PAC1 receptor pre-synaptically modulates hippocampal glutamatergic transmission acting through ACh. Therefore, administration of PACAP at very low doses might be envisaged in cognitive diseases with reduced cholinergic transmission.
Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández de Elche, San Juan de Alicante, Spain.
Valeria
V
Pecoraro
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.
Lara Maria
LM
Sardone
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.
Mariangela
M
Chisari
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.
Flora
F
Licata
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.
Guido
G
Li Volsi
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy.
Vincenzo
V
Perciavalle
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Italy. Electronic address: ciranna@unict.it.
Lucia
L
Ciranna
Department of Clinical and Experimental Medicine, University of Messina, Italy.
Lara
L
Costa
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D046509:Tissue Culture Techniques
D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018091:Receptors, AMPA; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D018698:Glutamic Acid; D000109:Acetylcholine
AMPA; PACAP; acetylcholine; glutamate; neuropeptide; synaptic transmission