| First Author | Zhou W | Year | 2019 |
| Journal | Nat Neurosci | Volume | 22 |
| Issue | 2 | Pages | 205-217 |
| PubMed ID | 30664766 | Mgi Jnum | J:277526 |
| Mgi Id | MGI:6313568 | Doi | 10.1038/s41593-018-0311-1 |
| Citation | Zhou W, et al. (2019) Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection. Nat Neurosci 22(2):205-217 |
| abstractText | 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 alpha2 (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. |
