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 NCOR1/2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABRA2 expression in lateral hypothalamus GABAergic neurons (LH
GABA
). 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, while 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 defects. These findings identify a hypothalamus–hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.
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