HDAC3 Epigenetic Suppression by Electroacupuncture Restores AMPA Receptor Function and Synaptic Plasticity in...

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by continuous cognitive deterioration, primarily resulting from the accumulation of amyloid-β (Aβ) plaques and tau-induced neurofibrillary tangles (NFTs). Recent studies have also highlighted histone deacetylase 3 (HDAC3) as a critical suppressor of synaptic plasticity. Although pharmacological inhibition of HDAC3 has been shown to facilitate long-term potentiation (LTP), the precise relationship between HDAC3 activity and AMPA receptor signaling, key components in LTP induction and maintenance, remains insufficiently understood. Electroacupuncture (EA), known to modulate epigenetic markers like H3K9/H3K27 acetylation and HDAC3/4 activity, may offer therapeutic potential by targeting these pathways. Here, we investigated EA's effects on AD-related pathology in APP/PS1 transgenic mice, focusing on HDAC3-AMPA receptor interactions in synaptic plasticity. Behavioral assays (Morris water maze) and electrophysiological recordings revealed that EA improved spatial learning ability and reinstated LTP in APP/PS1 transgenic mice. Mechanistically, EA reduced hippocampal HDAC3 expression while upregulating GluR1/GluR2 subunits and increasing acetylated H3K9K14/H3 levels, suggesting HDAC3-mediated transcriptional regulation of AMPA receptor genes. Co-immunoprecipitation assays further supported HDAC3's physical interaction with AMPA receptor components. Crucially, conditional knockout of HDAC3 in neurons rescued both LTP impairments and memory deficits, reinforcing its pivotal role in synaptic dysfunction. Our findings unveil a novel epigenetic mechanism whereby EA mitigates AD-associated synaptic damage by suppressing HDAC3 and enhancing AMPA receptor-dependent plasticity, highlighting HDAC3 as a promising therapeutic target for AD intervention.