Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

• Verfasst von: Kupke, Janina [VerfasserIn]
• Verfasst von: Klimmt, Julien [VerfasserIn]
• Verfasst von: Mudlaff, Franziska [VerfasserIn]
• Verfasst von: Schwab, Maximilian [VerfasserIn]
• Verfasst von: Lutsik, Pavlo [VerfasserIn]
• Verfasst von: Plass, Christoph [VerfasserIn]
• Verfasst von: Sticht, Carsten [VerfasserIn]
• Verfasst von: Oliveira, Ana [VerfasserIn]
• Titel: Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1
• Verf.angabe: Janina Kupke, Julien Klimmt, Franziska Mudlaff, Maximilian Schwab, Pavlo Lutsik, Christoph Plass, Carsten Sticht and Ana M.M. Oliveira
• E-Jahr: 2024
• Jahr: 18 March 2024
• Umfang: 12 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 02.08.2024
• Titel Quelle: Enthalten in: Neuropsychopharmacology
• Ort Quelle: London : Springer Nature, 1993
• Jahr Quelle: 2024
• Band/Heft Quelle: 49(2024), 10, Seite 1528-1539
• ISSN Quelle: 1740-634X
• DOI: doi:10.1038/s41386-024-01843-0
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Epigenetics in the nervous system
• Sach-SW: Long-term memory
• Sach-SW: Synaptic plasticity
• K10plus-PPN: 1897548303

Abstract

Epigenetic factors are well-established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role of DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we demonstrated that Dnmt3a1, the predominant Dnmt in the adult brain, is required for long-term spatial object recognition and contextual fear memory. Using RNA sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were associated with functional and structural plasticity. Furthermore, we found that some of the identified genes are selectively dependent on Dnmt3a1, but not its isoform Dnmt3a2. Specifically, we identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 and further demonstrated the involvement of Nrp1 in hippocampus-dependent memory formation. Importantly, we found that Dnmt3a1 regulates hippocampus-dependent memory via Nrp1. In contrast, Nrp1 overexpression did not rescue memory impairments triggered by reduced Dnmt3a2 levels. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.