1. Academic Validation
  2. Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice

Blocking H2A.Z Incorporation via Tip60 Inhibition Promotes Systems Consolidation of Fear Memory in Mice

  • eNeuro. 2018 Nov 8;5(5):ENEURO.0378-18.2018. doi: 10.1523/ENEURO.0378-18.2018.
Klotilda Narkaj 1 Gilda Stefanelli 2 Malak Wahdan 2 Amber B Azam 1 Firyal Ramzan 2 Carl Frank David Steininger Jr 2 Brandon J Walters 3 Iva B Zovkic 1 2
Affiliations

Affiliations

  • 1 Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
  • 2 Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario L5L 1C6, Canada.
  • 3 Department of Neurosciences & Mental Health, the Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Abstract

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.

Keywords

H2A.Z; Tip60; chromatin; epigenetics; histone acetylation; histone variants.

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