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

Walters, Brandon J.; Zovkic, Iva B.

doi:10.1016/j.neuroscience.2015.05.005

Cited by 14 publications

(14 citation statements)

References 124 publications

(212 reference statements)

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“…We previously showed that H2A.Z depletion in the cortex influences memory 7 d, but not 24 h, after learning ( Zovkic et al, 2014 ), indicating that cortical contribution to memory recall becomes evident by 7 d. However, remote fear memories are widely considered to enter the maintenance stage at ∼30 d, when they are no longer dependent on the hippocampus ( Walters and Zovkic, 2015 ). Thus, to determine whether Tip60 inhibition is also involved in regulating the maintenance of remote memory, mice were injected with Nu9056 30 d after learning and tested for recall 1 h after the injection.…”

Section: Resultsmentioning

confidence: 99%

“…One contributing factor is the complexity of memory formation, both in terms of molecular mechanisms and the time scales at which memories form. Memory formation is a multistage process that begins with transient synaptic consolidation in the hippocampus, which lasts ∼3 h and is the focus of most studies ( Walters and Zovkic, 2015 ). This stage is accompanied by a prolonged period of systems consolidation (at least 7 d), during which memories are gradually transferred from short-term storage in the hippocampus for long-term maintenance in the cortex ( Frankland and Bontempi, 2005 ; Lesburguères et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

“…These drugs allowed us to achieve temporally specific inhibition of H2A.Z or acetylated H2A.Z (acH2A.Z) to tease apart their effects on recent (24 h) versus older (7 d) memory and remote (30 d) memory. The 7 d time point was selected because it represents an intermediate time point between recent and remote memory, when memories become increasingly independent of the hippocampus ( Frankland and Bontempi, 2005 ; Zovkic et al, 2014 ; Walters and Zovkic, 2015 ). Given that H2A.Z is a memory suppressor whose levels accumulate in the aging hippocampus ( Stefanelli et al, 2018 ), the identification of drugs that effectively manipulate H2A.Z levels have therapeutic implications for memory decline.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Narkaj¹,

Stefanelli²,

Wahdan³

et al. 2018

eNeuro

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Narkaj¹,

Stefanelli²,

Wahdan³

et al. 2018

eNeuro

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show abstract

“…In contrast to known deposition candidates, regulation of H3.3 removal from chromatin is poorly understood, and Maze et al provided the first evidence implicating proteasome-mediated H3.3 eviction and degradation in neurons. This novel role for the proteasome is particularly interesting in light of recent evidence for proteasomal regulation of learning and memory, as well as its regulation of H2A variants outside the brain (Walters and Zovkic, 2015). …”

mentioning

confidence: 99%

Memory-Associated Dynamic Regulation of the “Stable” Core of the Chromatin Particle

Zovkic

Sweatt

2015

Neuron

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“…Achieving this goal requires the ability to manipulate (both increase and decrease) gene expression. The regulation of gene function in the brain is highly dynamic and may be different across brain regions (Zovkic et al, 2013 ; Walters and Zovkic, 2015 ). Therefore, manipulating gene function in the brain poses particular challenges, in that gene manipulations should be temporally and spatially specific.…”

mentioning

confidence: 99%

Advanced In vivo Use of CRISPR/Cas9 and Anti-sense DNA Inhibition for Gene Manipulation in the Brain

et al. 2016

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Gene editing tools are essential for uncovering how genes mediate normal brain–behavior relationships and contribute to neurodegenerative and neuropsychiatric disorders. Recent progress in gene editing technology now allows neuroscientists unprecedented access to edit the genome efficiently. Although many important tools have been developed, here we focus on approaches that allow for rapid gene editing in the adult nervous system, particularly CRISPR/Cas9 and anti-sense nucleotide-based techniques. CRISPR/Cas9 is a flexible gene editing tool, allowing the genome to be manipulated in diverse ways. For instance, CRISPR/Cas9 has been successfully used to knockout genes, knock-in mutations, overexpress or inhibit gene activity, and provide scaffolding for recruiting specific epigenetic regulators to individual genes and gene regions. Moreover, the CRISPR/Cas9 system may be modified to target multiple genes at one time, affording simultaneous inhibition and overexpression of distinct genetic targets. Although many of the more advanced applications of CRISPR/Cas9 have not been applied to the nervous system, the toolbox is widely accessible, such that it is poised to help advance neuroscience. Anti-sense nucleotide-based technologies can be used to rapidly knockdown genes in the brain. The main advantage of anti-sense based tools is their simplicity, allowing for rapid gene delivery with minimal technical expertise. Here, we describe the main applications and functions of each of these systems with an emphasis on their many potential applications in neuroscience laboratories.

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

Cited by 14 publications

References 124 publications

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

Memory-Associated Dynamic Regulation of the “Stable” Core of the Chromatin Particle

Advanced In vivo Use of CRISPR/Cas9 and Anti-sense DNA Inhibition for Gene Manipulation in the Brain

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