DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity - PubMed (original) (raw)
DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity
Courtney A Miller et al. Neurobiol Learn Mem. 2008 May.
Abstract
A clear understanding is developing concerning the importance of epigenetic-related molecular mechanisms in transcription-dependent long-term memory formation. Chromatin modification, in particular histone acetylation, is associated with transcriptional activation, and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training. Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation, DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory formation. Here, we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition. These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.
Figures
Figure 1
DNMT inhibition blocks memory consolidation and histone acetylation. (a) Intra-CA1 infusion of 5-AZA immediately following contextual fear conditioning blocked consolidation, as evidenced by a lack of freezing at the 24 h test (N = 7, C/S + VEH; N = 9, C/S + 5-AZA). (b) Intra-CA1 infusion of 5-AZA immediately following contextual fear conditioning (C/S + 5-AZA) blocked AcH3 one hr post-training, but had no effect on context only controls (C + 5-AZA; N = 7 per group). (c) Intra-CA1 infusion of 5-AZA had no effect on the ERK phosphorylation induced by contextual fear conditioning. (N = 7 per group.) * P < 0.05. Error bars represent s.e.m.
Figure 2
HDAC inhibition prevents the memory deficit induced by DNMT inhibition. (a) Pre-training intra-CA1 infusions of NaB do not affect an animal’s ability to perceive and respond to footshock during training. The “VEH” group refers to animals that received pre-training vehicle infusions, but contains animals that then received either vehicle or 5-AZA post-training, after the percent freezing during training measurements were taken. The “NaB” group refers to animals that received pre-training NaB infusions, but contains animals that received either vehicle or 5-AZA post-training. (b) Intra-CA1 infusion of NaB prior to training blocked the memory consolidation deficit produced by 5-AZA infusion. (N = 7–8 per group.) * P < 0.05. (c) The rescue effect of HDAC inhibition on memory for contextual fear conditioning is long-lasting; present at not only 24 hours (Fig. 2A), but also seven days later. * P < 0.05. Error bars represent s.e.m.
Figure 3
HDAC inhibition prevents the LTP deficit induced by DNMT inhibition. (a) LTP was rescued by application of the HDAC inhibitor, TSA, prior to 5-AZA. (N = 10–17 per group; calibration is 1 mV and 5 ms.) (b) Input-output synaptic relation is normal in slices pretreated with 5-Aza, TSA or co-application of 5-Aza and TSA relative to their respective vehicles. Error bars represent s.e.m.
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References
- Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004;42:947–959. - PubMed
- Becker PB, Ruppert S, Schutz G. Genomic footprinting reveals cell type-specific DNA binding of ubiquitous factors. Cell. 1987;51:435–443. - PubMed
- Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL, Sweatt JD, Zoghbi HY. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Human Molecular Genetics. 2004;13:2679–2689. - PubMed
- Cross SH, Meehan RR, Nan X, Bird A. A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins. Nature Genetics. 1997;16:256–259. - PubMed
- Fischer A, Sananabenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature. 2007;447:178–182. - PubMed
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