Altered Memory Capacities and Response to Stress in p300/CBP-Associated Factor (PCAF) Histone Acetylase Knockout Mice

Tangui Maurice (1) , Florian Duclot (1) , Johann Meunier (1) , Gaëlle Naert (1) , Laurent Givalois (1) , Julie Meffre (1, 2) , Aurélie Célérier (2) , Chantal Jacquet (3) , Virginie Copois (4) , Nadir Mechti (4) , Keiko Ozato (5) , Céline Gongora (4)

1 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
2 PC - Plasticité cérébrale
3 IGMM - Institut de Génétique Moléculaire de Montpellier
4 IRIM - Institut de Recherche en Infectiologie de Montpellier
5 NIH - National Institutes of Health [Bethesda, MD, USA]

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.

Mots clés: histone acetylase PCAF; short-term memory; spatial memory; stress; age; behavioral phenotyping

Domaines: Neurosciences [q-bio.NC]

Tangui Maurice, Florian Duclot, Johann Meunier, Gaëlle Naert, Laurent Givalois, et al.. Altered Memory Capacities and Response to Stress in p300/CBP-Associated Factor (PCAF) Histone Acetylase Knockout Mice. Neuropsychopharmacology, 2008, 33 (7), pp.1584-1602. ⟨10.1038/sj.npp.1301551⟩. ⟨inserm-00218215⟩