Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA editing enzyme Adar1 is required for fear extinction

DNA forms conformational states beyond the right-handed double-helix; however, the functional relevance of these non-canonical structures in the brain remains unknown. 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 novel mechanism of learning-induced gene regulation dependent on both proteins which recognize DNA structure, and the state.