HDAC1 Regulates Fear Extinction in Mice

Abstract

Histone acetylation has been implicated with the pathogenesis of neuropsychiatric disorders and targeting histone deacetylases (HDACs) using HDAC inhibitors was shown to be neuroprotective and to initiate neuroregenerative processes. However, little is known about the role of individual HDAC proteins during the pathogenesis of brain diseases. HDAC1 was found to be upregulated in patients suffering from neuropsychiatric diseases. Here, we show that virus-mediated overexpression of neuronal HDAC1 in the adult mouse hippocampus specifically affects the extinction of contextual fear memories, while other cognitive abilities were unaffected. In subsequent experiments we show that under physiological conditions, hippocampal HDAC1 is required for extinction learning via a mechanism that involves H3K9 deacetylation and subsequent trimethylation of target genes. In conclusion, our data show that hippocampal HDAC1 has a specific role in memory function.

HDAC1 links early life stress to schizophrenia-like phenotypes

“…The human genome encodes 11 zinc-dependent HDACs that are grouped into three classes. The emerging picture suggests that mainly class I HDACs might be suitable targets to treat brain diseases (12,14). HDAC inhibitors are also discussed as novel targets to treat schizophrenia (15)(16)(17).…”

“…or overexpressing neuronal Hdac1 from early developmental stages exhibit no cognitive phenotype (23). The lack of a phenotype might be due to compensatory mechanisms during development, because manipulating HDAC1 in the adult brain has been shown to affect specific forms of cognitive function (14,24).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…More recently, HDAC1 activity has been associated with fear memory extinction for the inhibition of excess fear. The overexpression of HDAC1 in the adult mouse hippocampus increased this specific form of learning [185]. Furthermore, the loss of HDAC4 (in 2-month-old mice) and HDAC5 (in 10-but not 2-month-old mice) impaired memory functions, with an alteration in the CxFC and the MWM tasks in both cases [186,187].…”

“…As hippocampal acetylation or HATs such as CBP/P300 are essential to form contextual fear, fear extinction also involves epigenetic mechanisms [185,[220][221][222]. Notably, as discussed above, HDAC1 regulates extinction learning via a mechanism involving H3K9 deacetylation and the subsequent trimethylation of target genes [185]. Interestingly, HDAC1 was up-regulated in postmortem brain samples from schizophrenic patients [223,224].…”

“…Fear extinction involves the gradual reduction in the fear response through the repeated presentation of a nonreinforced conditioned stimulus, which generates a new memory that competes with the original fear memory trace. As hippocampal acetylation or HATs such as CBP/P300 are essential to form contextual fear, fear extinction also involves epigenetic mechanisms [185,[220][221][222]. Notably, as discussed above, HDAC1 regulates extinction learning via a mechanism involving H3K9 deacetylation and the subsequent trimethylation of target genes [185].…”