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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA3 Region, Hippocampal / metabolism*
  • Databases, Factual
  • Excitatory Postsynaptic Potentials / genetics
  • GABAergic Neurons / metabolism*
  • Hypothalamus / metabolism*
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Memory / physiology*
  • Memory Disorders / genetics*
  • Memory Disorders / metabolism
  • Mice
  • Mice, Transgenic
  • Neural Pathways / metabolism
  • Neuronal Plasticity / physiology
  • Nuclear Receptor Co-Repressor 1 / genetics*
  • Nuclear Receptor Co-Repressor 1 / metabolism
  • Nuclear Receptor Co-Repressor 2 / genetics*
  • Nuclear Receptor Co-Repressor 2 / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism


  • Ncor1 protein, mouse
  • Ncor2 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Receptors, GABA-A