Open AccessDynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction
Author(s) -
Paul R. Marshall,
Qiongyi Zhao,
Xiang Li,
Wei Wei,
Ambika Periyakaruppiah,
Esmi L. Zajaczkowski,
Laura J. Leighton,
Sachithrani U. Madugalle,
Dean Basic,
Ziqi Wang,
Jiayu Yin,
Wei-Siang Liau,
Ankita Gupte,
Carl R. Walkley,
Timothy W. Bredy
Publication year - 2020
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-020-0627-5
Subject(s) - dna , extinction (optical mineralogy) , prefrontal cortex , rna , rna editing , fear conditioning , biology , neuroscience , genetics , gene , amygdala , paleontology , cognition
DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.