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

DDD study

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)205-217
Number of pages13
JournalNature Neuroscience
Volume22
Issue number2
DOIs
StatePublished - Feb 1 2019

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Lateral Hypothalamic Area
GABAergic Neurons
Co-Repressor Proteins
Memory Disorders
gamma-Aminobutyric Acid
Optogenetics
Neuronal Plasticity
Long-Term Potentiation
GABA-A Receptors
Interpersonal Relations
Intellectual Disability
Anxiety
Gene Expression
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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

In: Nature Neuroscience, Vol. 22, No. 2, 01.02.2019, p. 205-217.

Research output: Contribution to journalArticle

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