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Histone H3 lysine 9 di-methylation (H3K9me2) is an epigenetic repressive histone modification that was found at aberrant states in Alzheimer’s disease (AD) patient samples [1]. The addition of H3K9me2/3 is mainly catalyzed by lysine methyltransferase G9a, which functions as a heteromeric complex with G9a-like protein (GLP). G9a/GLP has other non-histone substrates, including itself. G9a/GLP is implicated in regulating synaptic plasticity, learning and memory [2, 3]. We have previously shown that G9a/GLP inhibition ameliorates exogenous Aß oligomer-induced synaptic plasticity deficits in rat hippocampal slices [3]. In this study, we further tested the effects of G9a/GLP inhibition on synaptic plasticity. We first tested whether G9a/GLP inhibition could rescue long-term potentiation (LTP) deficits in CA1 area of hippocampal slices of APP/PS1 mice (for materials and methods, see supplemental file). Field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of CA1 and two stimulating electrodes were used to stimulate two independent Schaffer Collateral inputs (Fig. 1a). We found that a strong tetanization protocol (STET) that typically induces an input-specific late-LTP only induced a transient potentiation (Fig. 1b). When APP/ PS1 hippocampal slices were perfused with G9a/GLP inhibitor BIX-01294 (BIX, 500 nM) or UNC-0642 (UNC, 150 nM) during LTP induction by STET, a long-lasting, inputspecific potentiation was observed (Fig. 1b). However, when translation inhibitor emetine (20 μM) was co-applied with BIX or UNC, STET only led to a transient potentiation (Fig. 1c). In all recordings, the control untetanized input S2 showed no significant changes in synaptic transmission. These results suggest that G9a/GLP blockade during LTP induction could rescue input-specific synaptic potentiation in APP/PS1 hippocampal slices through upregulating protein synthesis. Next, we examined whether G9a/GLP inhibition can restore long-term associative plasticity in hippocampal CA1 of APP/PS1 mice. The synaptic tagging and capture phenomenon is a pathway-specific form of associative plasticity in which a transient, translation-independent LTP (early-LTP) induced by weak stimulation (WTET) is stabilized into a long-lasting LTP (late-LTP) by a strong stimulation (STET) in another independent pathway within a specific time frame [3–5]. In APP/PS1 hippocampal slices, only a transient potentiation was observed after a STET and a WTET were applied 60 min apart to independent synaptic pathways S1 and S2 respectively (Fig. 1d).

translational neurodegeneration

Inhibition of lysine methyltransferase G9a/GLP reinstates long-term synaptic plasticity and synaptic tagging/capture by facilitating protein synthesis in the hippocampal CA1 area of APP/PS1 mouse model of Alzheimer’s disease