Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.

Abstract

We studied a mouse model of the haploinsufficiency form of Rubinstein-Taybi syndrome (RTS), an inheritable disorder caused by mutations in the gene encoding the CREB binding protein (CBP) and characterized by mental retardation and skeletal abnormalities. In these mice, chromatin acetylation, some forms of long-term memory, and the late phase of hippocampal long-term potentiation (L-LTP) were impaired. We ameliorated the L-LTP deficit in two ways: (1) by enhancing the expression of CREB-dependent genes, and (2) by inhibiting histone deacetyltransferase activity (HDAC), the molecular counterpart of the histone acetylation function of CBP. Inhibition of HDAC also reversed the memory defect observed in fear conditioning. These findings suggest that some of the cognitive and physiological deficits observed on RTS are not simply due to the reduction of CBP during development but may also result from the continued requirement throughout life for both the CREB co-activation and the histone acetylation function of CBP.

• Authors: Juan M Alarcón, Gaël Malleret, Khalid Touzani, Svetlana Vronskaya, Shunsuke Ishii, Eric R Kandel, Angel Barco
• Journal: Neuron (Neuron) Vol. 42 Issue 6 Pg. 947-59 (Jun 24 2004) ISSN: 0896-6273 [Print] United States
• PMID: 15207239 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2004 Cell Press

Chemical References

• Brain-Derived Neurotrophic Factor
• Chromatin
• Nuclear Proteins
• Phosphodiesterase Inhibitors
• Proto-Oncogene Proteins c-fos
• Synaptophysin
• Trans-Activators
• Dynorphins
• CREB-Binding Protein
• CREBBP protein, human
• Crebbp protein, mouse
• Rolipram

Topics

• Acetylation
• Analysis of Variance
• Animals
• Blotting, Western (methods)
• Brain-Derived Neurotrophic Factor (metabolism)
• CREB-Binding Protein
• Cell Line
• Chromatin (classification, metabolism)
• Conditioning, Psychological
• Disease Models, Animal
• Dynorphins (metabolism)
• Electrophysiology
• Embryo, Mammalian
• Excitatory Postsynaptic Potentials (drug effects)
• Fear
• Female
• Gene Expression
• Heterozygote
• Hippocampus (cytology, drug effects, physiopathology)
• Humans
• Immunohistochemistry
• In Situ Hybridization
• In Vitro Techniques
• Kidney
• Long-Term Potentiation (drug effects, genetics, physiology)
• Male
• Maze Learning
• Memory (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Motor Activity
• Neural Inhibition
• Neurons (drug effects, physiology)
• Nuclear Proteins (genetics, metabolism)
• Phosphodiesterase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-fos (metabolism)
• Psychomotor Performance
• Reaction Time
• Recognition, Psychology
• Rolipram (pharmacology)
• Rubinstein-Taybi Syndrome (genetics, physiopathology)
• Synaptophysin (metabolism)
• Time Factors
• Trans-Activators (genetics, metabolism)
• Transfection