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Browsing by Subject "Nuclear Receptor Co-Repressor 1"
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Item Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection(Springer Nature, 2019-02) Zhou, Wenjun; He, Yanlin; Rehman, Atteeq U.; Kong, Yan; Hong, Sungguan; Ding, Guolian; Yalamanchili, Hari Krishna; Wan, Ying-Wooi; Paul, Basil; Wang, Chuhan; Gong, Yingyun; Zhou, Wenxian; Liu, Hao; Dean, John; Scalais, Emmanuel; O’Driscoll, Mary; Morton, Jenny E.V.; Hou, Xinguo; Wu, Qi; Tong, Qingchun; Liu, Zhandong; Liu, Pengfei; Xu, Yong; Sun, Zheng; Biostatistics, IU School of MedicineNuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.