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

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 NCOR1/2 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.

A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

“…with strong links to psychiatric and neurodevelopmental disorders and synaptic function and neuronal excitability ( Fig. 5b) [62][63][64][65][66][67][68][69][70][71][72]. Of note, two different isoforms from Circadian Locomotor Output Cycles Kaput (Clock), a gene involved in circadian rhythms and linked to depression and BD [73][74][75], were found to be differently altered (one more than threefold reduced and one more than fourfold increased) by circHomer1a knockdown (Fig.…”

Identifying Integrative Molecular Pathways for Predictive Modeling of Infectious Disease

“…The hypothalamus, located on the inferior portion of the diencephalon, contains a cluster of nuclei and tracts, and functions as the central controller influencing many body functions including those of the autonomic and endocrine systems [11]. Metabolism, heart rate, digestion, blood pressure, body temperature, limbic response, as well as stress-related factors, respiration [8], cerebral function, including memory [28], are all influenced by the hypothalamus. Sensory neurons terminate in the hypothalamus and in response efferent fibers extend into the brainstem and the spinal cord, where they synapse with neurons for example of the autonomic nervous system [25].…”

Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain

“…The depletion of NCOR1/2 in GABAergic neurons with Vgat-Cre (NS-V mice) causes learning and memory deficits ( 70 ). The electrophysiological analysis identifies the hyperexcitability of GABAergic neurons in the lateral hypothalamus (LH) in NS-V mice.…”

“…Ribosome profiling identified that GABA A receptor subunits are downregulated in the LH GABA neurons in NS-V mice. This hypothalamic excitatory/inhibitory (E/I) imbalance impairs synaptic plasticity in the hippocampus CA3 region through a monosynaptic LH GABA -to-CA3 neural projection, which accounts for the neurocognitive dysfunction in NS-V mice ( 70 ).…”

“…NCOR1/2 is required for the enzyme activity of HDAC3. In a whole-body knock-in mouse model with mutations in the NCOR1/2 DADs that disrupt their binding to HDAC3 (NS-DADm mice), HDAC3 enzymatic activity is abolished in the brain and other tissues tested ( 70 ). These mice display social interaction deficits, impaired spatial learning and recognition memory, reduced anxiety, and enhanced locomotor coordination ( Table 1 ).…”