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

• Published in: Nature neuroscience Vol. 22; no. 2; pp. 205 - 217
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 38; 38/39; 631/378; 631/443; 64; 64/60; Activation; Animal Genetics and Genomics; Animals; Anxiety; Behavioral Sciences; Biochemistry; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Brain research; CA3 Region, Hippocampal - metabolism; Databases, Factual; Depletion; Excitatory Postsynaptic Potentials - genetics; GABA; GABAergic Neurons - metabolism; Gene expression; Genes; Hippocampus; Histone deacetylase; Hypothalamus; Hypothalamus (lateral); Hypothalamus - metabolism; Intellectual Disability - genetics; Intellectual Disability - metabolism; Long-term potentiation; Medical research; Medical schools; Memory; Memory - physiology; Memory Disorders - genetics; Memory Disorders - metabolism; Mice; Mice, Transgenic; Mutation; Neural Pathways - metabolism; Neurobiology; Neurodevelopmental disorders; Neuronal Plasticity - physiology; Neurons; Neurosciences; Nuclear Receptor Co-Repressor 1 - genetics; Nuclear Receptor Co-Repressor 1 - metabolism; Nuclear Receptor Co-Repressor 2 - genetics; Nuclear Receptor Co-Repressor 2 - metabolism; Nuclear receptors; Projection; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; SMRT protein; Social factors; Social interactions; Synaptic plasticity; γ-Aminobutyric acid A receptors
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-018-0311-1

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 GABA A receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LH GABA ) neurons. This was associated with LH GABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LH GABA to CA3 GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LH GABA or CA3 GABA 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. Zhou et al. show that NCORs regulate memory and synaptic plasticity through a GABAergic hypothalamus–hippocampus projection in mice, and that variants in NCOR1 and NCOR2 are linked to intellectual disability and neurodevelopmental defects in humans.