Inhibition of Histone Methyltransferases EHMT1/2 Reverses Amyloid- β-Induced Loss of AMPAR Currents in Human Stem Cell-Derived Cortical Neurons

: Emerging evidence suggests that epigenetic dysregulation of gene expression is one of the key molecular mechanisms of neurodegeneration and Alzheimer's disease (AD). However, little is known about the role of epigenetic dysregulation on synaptic dysfunction in humans, because of the difficulties of obtaining live human neurons. Here we generated mature human cortical neurons differentiated from human embryonic stem cells, and exposed them to amyloid-β (Aβ). We found that the histone methyltransferase, EHMT1, which catalyzes histone lysine 9 dimethylation (H3K9me2, a mark for gene repression), was significantly elevated in Aβ-treated human stem cell-derived neurons. Aβ treatment led to a significant reduction of AMPAR-mediated whole-cell current and excitatory postsynaptic current. Application of BIX01294, a selective inhibitor of EHMT1/2, restored AMPAR currents and glutamatergic synaptic transmission in Aβ-treated human cortical neurons. These results suggest that inhibition of the aberrant histone methylation is a novel approach to reverse Aβ-induced synaptic deficits in human neurons.