脱甲基酶
神经科学
突触可塑性
谷氨酸受体
兴奋性突触后电位
树突棘
海马体
生物
化学
表观遗传学
海马结构
抑制性突触后电位
基因
生物化学
受体
作者
Yanan Wang,Nitin Khandelwal,Shuiqiao Liu,Mi Zhou,Lei Bao,Jennifer E. Wang,Ashwani Kumar,Chao Xing,Jay R. Gibson,Yingfei Wang
标识
DOI:10.1038/s41380-022-01750-0
摘要
The excitatory neurotransmitter glutamate shapes learning and memory, but the underlying epigenetic mechanism of glutamate regulation in neuron remains poorly understood. Here, we showed that lysine demethylase KDM6B was expressed in excitatory neurons and declined in hippocampus with age. Conditional knockout of KDM6B in excitatory neurons reduced spine density, synaptic vesicle number and synaptic activity, and impaired learning and memory without obvious effect on brain morphology in mice. Mechanistically, KDM6B upregulated vesicular glutamate transporter 1 and 2 (VGLUT1/2) in neurons through demethylating H3K27me3 at their promoters. Tau interacted and recruited KDM6B to the promoters of Slc17a7 and Slc17a6, leading to a decrease in local H3K27me3 levels and induction of VGLUT1/2 expression in neurons, which could be prevented by loss of Tau. Ectopic expression of KDM6B, VGLUT1, or VGLUT2 restored spine density and synaptic activity in KDM6B-deficient cortical neurons. Collectively, these findings unravel a fundamental mechanism underlying epigenetic regulation of synaptic plasticity and cognition.
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