Cortical synaptic plasticity and remote memory require neuronal CCCTC-binding factor (CTCF), a central regulator of 3D chromatin architecture

摘要

Al is likely engaged by other processes, such as arousal, saliency, or behavioral adjustments. Various epigenetic mechanisms are known to be important for long-term memory, but how the three-dimensional (3D) chromatin architecture and its regulator molecules contribute to neuronal plasticity and memory consolidation are still largely unknown. To assess memory upon the perturbation of the 3D chromatin struc- ture, we chose the CCCTC-binding factor (CTCF), a seven-zinc finger protein well known for its role as a transcription factor and a chro- matin regulator, and generated conditional knockout (cKO) mice in which CTCF is lost in neurons during adulthood. Our CTCF cKO mice showed normal recent memory in the contextual fear con- ditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Under- lying the remote memory-specific phenotypes, we observed that loss of CTCF disrupts cortical long-term potentiation (LTP), but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA-sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated chromatin regulation in neurons.