Ablation of CBP in forebrain principal neurons causes modest memory and transcriptional defects and a dramatic reduction of histone acetylation but does not affect cell viability.

Abstract

Rubinstein-Taybi syndrome (RSTS) is an inheritable disease associated with mutations in the gene encoding the CREB (cAMP response element-binding protein)-binding protein (CBP) and characterized by growth impairment, learning disabilities, and distinctive facial and skeletal features. Studies in mouse models for RSTS first suggested a direct role for CBP and histone acetylation in cognition and memory. Here, we took advantage of the genetic tools for generating mice in which the CBP gene is specifically deleted in postmitotic principal neurons of the forebrain to investigate the consequences of the loss of CBP in the adult brain. In contrast to the conventional CBP knock-out mice, which exhibit very early embryonic lethality, postnatal forebrain-restricted CBP mutants were viable and displayed no overt abnormalities. We identified the dimer of histones H2A and H2B as the preferred substrate of the histone acetyltransferase domain of CBP. Surprisingly, the loss of CBP and subsequent histone hypoacetylation had a very modest impact in the expression of a number of immediate early genes and did not affect neuronal viability. In addition, the behavioral characterization of these mice dissociated embryonic and postnatal deficits caused by impaired CBP function, narrowed down the anatomical substrate of specific behavioral defects, and confirmed the special sensitivity of object recognition memory to CBP deficiency. Overall, our study provides novel insights into RSTS etiology and clarifies some of the standing questions concerning the role of CBP and histone acetylation in activity-driven gene expression, memory formation, and neurodegeneration.

• Authors: Luis M Valor, Matias M Pulopulos, Maria Jimenez-Minchan, Roman Olivares, Beat Lutz, Angel Barco
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 5 Pg. 1652-63 (Feb 02 2011) ISSN: 1529-2401 [Electronic] United States
• PMID: 21289174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• CREB-Binding Protein

Topics

• Acetylation
• Animals
• Blotting, Western
• CREB-Binding Protein (genetics, metabolism)
• Cell Line, Transformed
• Cell Survival
• Conditioning, Classical
• Disease Models, Animal
• HEK293 Cells
• Histones (metabolism)
• Humans
• Immunohistochemistry
• Locomotion
• Maze Learning
• Memory
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (metabolism)
• Plasmids
• Polymerase Chain Reaction
• Prosencephalon (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Rubinstein-Taybi Syndrome (genetics, metabolism)
• Transfection