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

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 TSA increased H2A.Z acetylation without influencing total H2A.Z in cultured hippocampal neurons. Tip60 (but not HDAC) inhibition 23h after learning enhanced remote (tested at 7 days) and not recent (tested at 24 hours) contextual fear memory in mice. In contrast, Tip60 inhibition 30 days after learning impaired recall of remote memory after 1h, but protected the memory from further declining 24h later. These data provide the first evidence of a delayed post-learning role for histone variants in supporting memory transfer during systems consolidation. Significance Statement Understanding the molecular basis of memory is fundamental for developing novel therapies for memory decline, but progress is impeded by the presence of multiple stages of memory formation that may involve unique molecular events. Our data identify a new time point, 24h after learning, at which H2A.Z manipulation selectively impacts remote memory without influencing recent memory. This finding advances our understanding of memory for several reasons: 1) It demonstrates that ongoing epigenetic changes exert stage-specific outcomes on memory formation, and 2) It provides the first pharmacological tool for manipulating H2A.Z binding. Moreover, we show that Tip60 influences memory through effects that involve H2A.Z, which suggests that recent studies of Tip60-mediated plasticity may include actions on this histone.