RT Journal Article
SR Electronic
T1 Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0378-18.2018
DO 10.1523/ENEURO.0378-18.2018
VO 5
IS 5
A1 Klotilda Narkaj
A1 Gilda Stefanelli
A1 Malak Wahdan
A1 Amber B. Azam
A1 Firyal Ramzan
A1 Carl Frank David Steininger, Jr
A1 Brandon J. Walters
A1 Iva B. Zovkic
YR 2018
UL http://www.eneuro.org/content/5/5/ENEURO.0378-18.2018.abstract
AB Memory formation is a protracted process that initially involves the hippocampus and becomes increasingly dependent on the cortex over time, but the mechanisms of this transfer are unclear. We recently showed that hippocampal depletion of the histone variant H2A.Z enhances both recent and remote memories, but the use of virally mediated depletion reduced H2A.Z levels throughout testing, making its temporally specific function unclear. Given the lack of drugs that target histone variants, we tested existing drugs for efficacy against H2A.Z based on their targeting of known H2A.Z regulators. The Tip60 (part of H2A.Z deposition complex) inhibitor Nu9056 reduced H2A.Z binding, whereas the histone deacetylase (HDAC) inhibitor Trichostatin-A increased H2A.Z acetylation without influencing total H2A.Z in cultured hippocampal neurons. Tip60 (but not HDAC) inhibition 23 h after learning enhanced remote (tested at 7 d) and not recent (tested at 24 h) contextual fear memory in mice. In contrast, Tip60 inhibition 30 d after learning impaired recall of remote memory after 1 h, but protected the memory from further decline 24 h later. These data provide the first evidence of a delayed postlearning role for histone variants in supporting memory transfer during systems consolidation.