Cognitive function in health and disease: the role of epigenetic mechanisms.
Epigenetic mechanisms regulate the interaction between the genome and the environment and have been implicated in the etiology of various brain diseases. One type of epigenetic modification, histone acetylation, is dynamically altered during memory formation. Histone acetylation is regulated by the activities of histone deacetylase (HDAC) and histone acetyltransferase enzymes. The use of HDAC inhibitors has emerged as a promising new strategy for the therapeutic intervention of neurodegenerative disease. We used a combination of pharmacological and mouse genetic approaches that allowed us to identify HDAC2 as a specific negative regulator of synaptic plasticity and memory formation. Our results suggest that HDAC inhibitors enhance cognitive function by inhibiting HDAC2, which renders HDAC2 target genes more accessible to transcriptional activators and coactivators recruited by neuronal activity stimulation. The data presented at the 2011 Barcelona ADPD Conference delineate a novel and important role for HDAC2 activity in the cognitive impairments associated with neurodegenerative disease.
Picower Institute for Learning and Memory, Cambridge, Mass, USA.
Alison E
AE
Mungenast
Li-Huei
LH
Tsai
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000235:genetics*; D010770:Phosphotransferases
C492236:Cdk5r1 protein, mouse; D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D056464:Histone Deacetylase 2