title: Histone deacetylase inhibition prevents the impairing effects of hippocampal gastrin-releasing peptide receptor antagonism on memory consolidation and extinction.
abstract: Hippocampal gastrin-releasing peptide receptors (GRPR) regulate memory formation and extinction, and disturbances in GRPR signaling may contribute to cognitive impairment associated with neurodevelopmental disorders. Histone acetylation is an important epigenetic mechanism that regulates gene expression involved in memory formation, and histone deacetylase inhibitors (HDACis) rescue memory deficits in several models. The present study determined whether inhibiting histone deacetylation would prevent memory impairments produced by GRPR blockade in the hippocampus. Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or the HDACi sodium butyrate (NaB) shortly before inhibitory avoidance (IA) training, followed by an infusion of either SAL or the selective GRPR antagonist RC-3095 immediately after training. In a second experiment, the infusions were administered before and after a retention test trial that served as extinction training. As expected, RC-3095 significantly impaired consolidation and extinction of IA memory. More importantly, pretraining administration of NaB, at a dose that had no effect when given alone, prevented the effects of RC-3095. In addition, the combination of NaB and RC-3095 increased hippocampal levels of the brain-derived neurotrophic factor (BDNF). These findings indicate that HDAC inhibition can protect against memory impairment caused by GRPR blockade.
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Petry
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Arethuza S
authors.initials: AS
authors.lastname: Dornelles
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Martina
authors.initials: M
authors.lastname: Lichtenfels
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Fernanda E
authors.initials: FE
authors.lastname: Valiati
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Children's Cancer Institute, Porto Alegre, RS, Brazil.
authors.forename: Caroline Brunetto
authors.initials: CB
authors.lastname: de Farias
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
authors.affiliation: Neuroscience Institute and Department of Psychology, Georgia State University, Atlanta, GA, USA.
authors.forename: Marise B
authors.initials: MB
authors.lastname: Parent
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: rafael.roesler@pq.cnpq.br.
authors.forename: Rafael
authors.initials: R
authors.lastname: Roesler
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001839:Bombesin / Q000031:analogs & derivatives / Q000633:toxicity; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D020148:Butyric Acid / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005108:Extinction, Psychological / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors; D018709:Statistics, Nonparametric
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010446:Peptide Fragments; D018004:Receptors, Bombesin; D020148:Butyric Acid; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D006655:Histone Deacetylases; D001839:Bombesin
keywords: Brain-derived neurotrophic factor; Gastrin-releasing peptide receptor; Hippocampus; Histone deacetylase; Memory consolidation; Memory extinction