Abstract
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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Data availability
The RNA-seq data were deposited at the GEO database with accession number GSE197117.
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Acknowledgements
We thank Drs. Woo-Ping Ge and Kimberly Huber for advice on eletrophysology studies, Dr. Stuart H. Orkin at Harvard Medical School for providing Kdm6bfl/fl mice, and UT Southwestern core facilities including electron microscopy core, rodent behavior core, and live cell imaging core for experimental assistance (1P30 CA142543-01).
Funding
This work was supported by grants from the NIH (R35GM124693, R00NS078049, and R01AG066166) to YW.
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YNW and YW conceived and designed experiments and wrote the manuscript. YNW performed and analyzed most experiments. NK and JRG performed electrophysiological recordings and data analysis. SL helped perform some behavioral tests. MZ and LB helped experimental optimization and data interpretation. JEW assisted in breeding and genotyping of KDM6B cKO mice.
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Wang, Y., Khandelwal, N., Liu, S. et al. KDM6B cooperates with Tau and regulates synaptic plasticity and cognition via inducing VGLUT1/2. Mol Psychiatry 27, 5213–5226 (2022). https://doi.org/10.1038/s41380-022-01750-0
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DOI: https://doi.org/10.1038/s41380-022-01750-0
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