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.

核受体corepressor 1（NCOR1）和NCOR2（也称为SMRT）通过它们的脱乙酰基酶激活域（DAD）激活组蛋白脱乙酰基酶3来调​​节基因表达。我们显示具有DAD敲入突变的小鼠具有记忆缺陷，焦虑水平降低和社交互动减少。专门在GABA能神经元（NS-V小鼠）中消耗NCOR1和NORC2的小鼠概括了记忆缺陷，并降低了下丘脑外侧GABA能神经元（LH ^GABA）的GABA _A受体亚基α2（GABRA2）表达。通过单突触的LH ^GABA到CA3 ^GABA，这与LH ^GABA神经元过度兴奋和海马长时程增强受损有关投影。该投射的光遗传学激活引起记忆缺陷，而针对性操纵LH ^GABA或CA3 ^GABA神经元活性可逆转NS-V小鼠的记忆缺陷。我们描述了智力障碍或神经发育障碍患者的NCOR1，NCOR2或HDAC3的从头变异。这些发现确定了下丘脑-海马的投射，这可能通过NCOR介导的GABA信号调节将内分泌信号与突触可塑性联系起来。