Cognitive deficits triggered by early life stress: The role of histone deacetylase 1.
Studies showed that histone deacetylase (HDAC) inhibitors can reverse cognitive deficits found in neurodegenerative disorders and age-related memory decline. However, the role of HDACs in stress-induced cognitive deficits has not been investigated. In the stress-susceptible mouse strain Balb/c, early life stress triggers a persistent decrease in HDAC expression in the forebrain neocortex, including reduced expression of class I HDACs. The same mice show pronounced cognitive deficits in adulthood, namely deficits in working memory and attention set-shifting. Here we show that these mice also exhibit reduced association of HDAC1 with promotor III of the brain-derived neurotrophic factor (Bdnf) gene, and that cognitive testing leads to abnormally increased Bdnf mRNA expression. A pharmacological reduction of Bdnf-tropomyosine kinase B receptor signaling effectively reverses the cognitive deficits, indicating that enhanced transcriptional activation of the Bdnf gene contributes to their emergence. In contrast to Balb/c mice, C57Bl/6 mice only develop attention set-shifting deficits when raised by Balb/c foster mothers during the time the pups are exposed to early life stress. HDAC1 levels at Bdnf promotor III are unaltered in such C57Bl/6 mice, although they exhibit decreased levels of HDAC1 at the promotor of the early-growth response gene 2 (Egr2) and abnormally increased Egr2 mRNA expression after cognitive testing. Hence, contrary to the beneficial effects of HDAC inhibition in neurodegenerative diseases, the reduced HDAC1 levels at promotors of distinct plasticity-associated genes predispose animals exposed to early life stress to enhanced expression of these genes upon cognitive challenge, an effect that negatively influences cognitive task performance.
Department of Psychiatry, Columbia University, New York, NY 10032, United States.
Samantha M
SM
Adler
Department of Psychiatry, Columbia University, New York, NY 10032, United States; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY 10032, United States. Electronic address: cs581@cumc.columbia.edu.
Claudia
C
Schmauss
D000818:Animals; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000503:physiopathology*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000502:physiology*
D056572:Histone Deacetylase Inhibitors; D020813:Receptor, trkB; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
Attention set-shifting; Bdnf promotor; Egr2 promotor; Gene expression; HDAC1 activity; Working memory