Histone deacetylase-2 is involved in stress-induced cognitive impairment via histone deacetylation and PI3K/AKT signaling pathway modification

Exposure to chronic stress upregulates blood glucocorticoid levels and impairs cognition via diverse epigenetic mechanisms, such as histone deacetylation. Histone deacetylation can lead to transcriptional silencing of many proteins involved in cognition and may also cause learning and memory dysfunction. Histone deacetylase-2 (HDAC2) has been demonstrated to epigenetically block cognition via a reduction in the histone acetylation level; however, it is unknown whether HDAC2 is involved in the cognitive decline induced by chronic stress. To the best of authors' knowledge, this is the first study to demonstrate that the stress hormone corticosteroid upregulate HDAC2 protein levels in neuro-2a cells and cause cell injuries. HDAC2 knockdown resulted in a significant amelioration of the pathological changes in N2a cells via the upregulation of histone acetylation and modifications in the phosphoinositide 3-kinase/protein kinase B signaling pathway. In addition, the HDAC2 protein levels were upregulated in 12-month-old female C57BL/6J mice under chronic stress in vivo. Taken together, these findings suggested that HDAC2 may be an important negative regulator involved in chronic stress-induced cognitive impairment.