Abstract
Aging is associated with impaired plasticity and memory. Altered epigenetic mechanisms are implicated in the impairment of memory with advanced aging. Histone deacetylase 3 (HDAC3) is an important negative regulator of memory. However, the role of HDAC3 in aged neural networks is not well established. Late long-term potentiation (late-LTP), a cellular correlate of memory and its associative mechanisms such as synaptic tagging and capture (STC) were studied in the CA1 area of hippocampal slices from 82–84 week old rats. Our findings demonstrate that aging is associated with deficits in the magnitude of LTP and impaired STC. Inhibition of HDAC3 augments the late-LTP and re-establishes STC. The augmentation of late-LTP and restoration of STC is mediated by the activation of nuclear factor kappa B (NFκB) pathway. We provide evidence for the promotion of associative plasticity in aged neural networks by HDAC3 inhibition and hence propose HDAC3 and NFκB as the possible therapeutic targets for treating age -related cognitive decline.
Highlights
Spectrum HDAC inhibitors mostly affect Class I HDACs with little effect on Class II HDACs22
Age associated memory impairment has been reported to be correlated with deficits in LTP12,13,37
The decrease in the magnitude of long-term potentiation (LTP) observed in our study is consistent with the earlier reports[2,11,31]
Summary
Spectrum HDAC inhibitors mostly affect Class I HDACs with little effect on Class II HDACs22. Selective inhibition of HDAC3 enhances the memory[26]. During the induction of LTP, NFκ B gets activated and induces the expression of genes such as bdnf, Zif[268], transthyretin and fos, which are implicated in memory[29,30]. We investigated the possible involvement of HDAC3 in LTP and STC process in the aged hippocampal neural network since HDAC3 has higher expression in the hippocampus[23,24]. Inhibition of HDAC3 during the induction of late plasticity enhanced the magnitude of LTP and re-established associative plasticity in aged neural networks. Our findings highlight that the inhibition of HDAC3 in aged neural network is beneficial for re-establishing associative plasticity through the activation of NFκ B pathway
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