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Nat Neurosci. 2019 Feb;22(2):205-217. doi: 10.1038/s41593-018-0311-1. Epub 2019 Jan 21.

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

Author information

1
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA.
2
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
3
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
4
New York Genome Center, New York, NY, USA.
5
Department of Chemistry, Chung-Ang University, Seoul, South Korea.
6
Jan and Dan Duncan Neurological Research Institute, Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
8
Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
9
Clinical Genetics Service, NHS Grampian, Aberdeen, Scotland, UK.
10
Pediatric Neurology, Centre Hospitalier de, Luxembourg, Luxembourg.
11
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, UK.
12
Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China.
13
Center for Metabolic and Degenerative Disease, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
14
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. pengfeil@bcm.edu.
15
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. yongx@bcm.edu.
16
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. yongx@bcm.edu.
17
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA. zheng.sun@bcm.edu.
18
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. zheng.sun@bcm.edu.

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 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.

PMID:
30664766
PMCID:
PMC6361549
[Available on 2019-07-21]
DOI:
10.1038/s41593-018-0311-1

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