NCOR1/2 loss of function impairs memory through a novel GABAergic hypothalamus–CA3 projection

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.