title: Endogenous inhibition of hippocampal LTD and depotentiation by vasoactive intestinal peptide VPAC1 receptors.
abstract: Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal-dependent learning in rodents. Homosynaptic long-term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low-frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac-Tyr(1) , D-Phe(2) GRF (1-29), and the selective VPAC1 receptor antagonist, PG 97-269, but not the selective VPAC2 receptor antagonist, PG 99-465. This action was mimicked by an anti-VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase-activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6-38) enhanced depotentiation, but not LTD. VPAC1 receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABAA antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC1 receptor-mediated mechanisms and suggest that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC1 receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy.
authors.affiliation: Instituto de Farmacologia e Neurociências, Faculdade de Medicina e Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Cunha-Reis
authors.forename: Maria de Fatima
authors.initials: Mde F
authors.lastname: Aidil-Carvalho
authors.forename: Joaquim A
authors.initials: JA
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D002491:Central Nervous System Agents / Q000494:pharmacology; D004558:Electric Stimulation; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D017208:Rats, Wistar; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D002491:Central Nervous System Agents; C110307:PG 97-269; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C075647:pituitary adenylate-cyclase-activating-peptide (6-38); D014660:Vasoactive Intestinal Peptide
keywords: LTD; VIP; VPAC1 receptor; depotentiation; hippocampus