title: Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice.
abstract: Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.
authors.affiliation: Université Montpellier II, Montpellier, France. Tangui.Maurice@univ-montp2.fr
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.forename: Florian
authors.initials: F
authors.lastname: Duclot
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Naert
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
authors.forename: Julie
authors.initials: J
authors.lastname: Meffre
authors.forename: Aurélie
authors.initials: A
authors.lastname: Célérier
authors.forename: Chantal
authors.initials: C
authors.lastname: Jacquet
authors.forename: Virginie
authors.initials: V
authors.lastname: Copois
authors.forename: Nadir
authors.initials: N
authors.lastname: Mechti
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Céline
authors.initials: C
authors.lastname: Gongora
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004644:Emotions / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D005260:Female; D006624:Hippocampus / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010364:Pattern Recognition, Visual / Q000502:physiology; D012737:Sex Factors; D013315:Stress, Psychological / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D050880:p300-CBP Transcription Factors / Q000172:deficiency*; D000099224:p300-CBP-Associated Factor