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Title: Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection

Author
item ZHOU, WENJUN - Baylor College Of Medicine
item HE, YANLIN - Children'S Nutrition Research Center (CNRC)
item REHMAN, ATTEEQ - Baylor College Of Medicine
item KONG, YAN - Baylor College Of Medicine
item HONG, SUNGGUAN - Baylor College Of Medicine
item DING, GUOLIAN - Baylor College Of Medicine
item YALAMANCHILI, HARI KRISHNA - Baylor College Of Medicine
item WAN, YING-WOOI - Baylor College Of Medicine
item PAUL, BASIL - Baylor College Of Medicine
item WANG, CHUHAN - Baylor College Of Medicine
item GONG, YINGYUN - Baylor College Of Medicine
item ZHOU, WENXIAN - Indiana University School Of Health & Rehabilitation
item LIU, HAO - Indiana University School Of Health & Rehabilitation
item HOU, XINGUO - Shandong University
item WU, QI - Children'S Nutrition Research Center (CNRC)
item TONG, QINGCHUN - University Of Texas Health Science Center
item LIU, ZHANDONG - Texas Children'S Hospital
item LIU, PENGFEI - Baylor College Of Medicine
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item SUN, ZHENG - Baylor College Of Medicine

Submitted to: Nature Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/30/2018
Publication Date: 1/21/2019
Citation: Zhou, W., He, Y., Rehman, A.U., Kong, Y., Hong, S., Ding, G., Yalamanchili, H., Wan, Y., Paul, B., Wang, C., Gong, Y., Zhou, W., Liu, H., Hou, X., Wu, Q., Tong, Q., Liu, Z., Liu, P., Xu, Y., Sun, Z. 2019. Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus–CA3 projection. Nature Neuroscience. 22:205-217.

Interpretive Summary: Cognitive dysfunctions are associated many metabolic disorders such as obesity and diabetes. However, the mechanisms for this association remain unclear. Here we discovered a novel neural circuit between the brain feeding center and the memory center and revealed key molecules, NCOR1 and NCOR2, that regulate the activities of this circuit and therefore modulate the memory of mice. These findings suggested that this neural circuit and/or NCOR1/2 could be potential targets for treatment of cognitive dysfunctions.

Technical Abstract: Nuclear 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 a2 (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.