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J Neurosci. 2018 May 30;38(22):5042-5052. doi: 10.1523/JNEUROSCI.2738-17.2018. Epub 2018 Apr 30.

Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF).

Author information

1
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea.
2
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea.
3
Salk Institute for Biological Studies, La Jolla, California 92130.
4
Department of Anatomy, Graduate School of Medicine, Kyungpook National University, Daegu 700-422, Korea.
5
Department of Cell Biology and Genetics, 3000 CA Rotterdam, The Netherlands.
6
Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea, and.
7
Department of Life and Nanopharmaceutical Sciences, Department of Maxillofacial Biomedical Engineering, School of Dentistry, Kyung Hee University, Seoul 02447, South Korea.
8
Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, South Korea, kaang@snu.ac.kr.

Abstract

The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical 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 gene regulation in neurons, whereas recent memory formation in the hippocampus does not.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.

KEYWORDS:

3D genome architecture; CTCF; cortical plasticity; remote memory; systems consolidation

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