| Autor: |
Burns AM; Laboratory of Neuroepigenetics, School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland., Farinelli-Scharly M; Electrophysiology Platform, E-PHY-SCIENCE, 06410 Biot, France., Hugues-Ascery S; Electrophysiology Platform, E-PHY-SCIENCE, 06410 Biot, France., Sanchez-Mut JV; Laboratory of Neuroepigenetics, School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland., Santoni G; Laboratory of Neuroepigenetics, School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland., Gräff J; Laboratory of Neuroepigenetics, School of Life Sciences, Brain Mind Institute, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland. |
| Jazyk: |
angličtina |
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 May 31; Vol. 119 (22), pp. e2116797119. Date of Electronic Publication: 2022 May 25. |
| DOI: |
10.1073/pnas.2116797119 |
| Abstrakt: |
Long-term memory formation relies on synaptic plasticity, neuronal activity-dependent gene transcription, and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional, and epigenetic responses that are induced by CI-994, a class I HDACi, combined with contextual fear conditioning (CFC) in mice. We show that CI-994–mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in fear learning. Furthermore, using a combination of bulk and single-cell RNA-sequencing, we find that, when paired with CFC, HDACi treatment engages synaptic plasticity-promoting gene expression more strongly in the hippocampus, specifically in the dentate gyrus (DG). Finally, using chromatin immunoprecipitation-sequencing (ChIP-seq) of DG neurons, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that underlie improved memory performance. Together, these results indicate that systemic HDACi administration amplifies brain region-specific processes that are naturally induced by learning. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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