Histone H2A.Z subunit exchange controls consolidation of recent and remote memory

Abstract

Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation1. Epigenetic mechanisms regulate both types of consolidation2–7, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain8–12 and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence forH2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.

Building up and knocking down: An emerging role for epigenetics and proteasomal degradation in systems consolidation

“…First, we assume that initial stages of memory consolidation occur in the hippocampus and that concurrent reactivation of the hippocampus and the cortex underlies systems consolidation. PFC is rapidly activated in response to learning (Lesburgueres et al, 2011;Zovkic et al, 2014), indicating that the hippocampus and the cortex process memories in parallel. However, impairments of both recent and remote memory produced by hippocampal lesions shortly after training (Frankland and Bontempi, 2005) suggest that the cortical memory trace is initially insufficient to support memory and must first undergo hippocampusdependent 'training' (Born and Wilhelm, 2012).…”

“…However, these processes tend to be studied independently and very little is known about the ways in which they interact. Moreover, the relative function and contribution of each level of regulation may change over the protracted time course of memory formation, which is characterized by modifications occurring in different brain regions at different points in time (Frankland and Bontempi, 2005;Miller et al, 2010;Lesburgueres et al, 2011;Zovkic et al, 2014). Here, we review the literature pertaining to the molecular mechanisms of systems consolidation, focusing particularly on epigenetic modifications that regulate the induction of gene activity and in protein degradation that is involved in resetting cellular states.…”

Genetic complementation analysis showed distinct contributions of the N‐terminal tail of H2A.Z to epigenetic regulations

“…All rights reserved tumorgenesis (Hua et al, 2008;Valdés-Mora et al, 2012;Kim et al, 2013), and cognate memory (Zovkic et al, 2014). H2A.Z is essential for the development of Drosophila and mice (Clarkson et al, 1999;Faast et al, 2001).…”

Histone acetylation in neuronal (dys)function

“…Moreover, new types of epigenetic modifications on DNA and histone variants are still being identified in the brain (129,130). In particular, evidence indicate a critical interplay between the different epigenetic modifications for the control of learning and memory processes, defining an epigenetic code for learning and memory, underlying the difficulty to study isolated modifications and their consequences.…”