2. Academic Validation
  3. Enhanced Protein Synthesis and Hippocampus-Dependent Memory via Inhibition of YTHDF2-Mediated m6A mRNA Degradation

Enhanced Protein Synthesis and Hippocampus-Dependent Memory via Inhibition of YTHDF2-Mediated m6A mRNA Degradation

  • Adv Sci (Weinh). 2025 Sep 17:e14926. doi: 10.1002/advs.202514926.
Kuan Li 1,  Chen Guo 2,  Xiaoli Wu 3,  Cuiting Wu 3 4,  Songfen Wu 1,  Si Su 1,  Min Wu 3 5,  Xidan Zhou 3,  Si Li 3 5,  Yihui Cui 2,  Tao Zhou 3 5 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital), Southern University of Science and Technology, Shenzhen, 518055, China.
  • 2 Department of Neurology of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 3 Shenzhen Neher Neural Plasticity Laboratory, Shenzhen Key Laboratory of Drug Addiction, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 4 Shenzhen Institutes of Advanced Technology, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology, Shenzhen, 518106, China.
  • 6 Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China.
PMID: 40959883 DOI: 10.1002/advs.202514926
Abstract

N6-methyladenosine (m6A) modification intricately regulates mRNA transportation, localization, and translation, significantly influencing learning and memory processes. However, the specific role of YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2)-mediated m6A mRNA degradation in learning and memory remains elusive. Utilizing a forebrain-specific conditional knockout mice model, it is discovered that the absence of YTHDF2 impedes the decay of m6A-modified mRNAs, resulting in heightened synaptic transmission in hippocampal neurons and improved hippocampus-dependent learning and memory. Unexpectedly, an increase in activity-dependent protein synthesis is also observed. Reintroduction of YTHDF2 expression or reduction of its downstream target, Semaphorin 4B (SEMA4B), in the hippocampus reverses the enhanced memory in conditional knockout mice, while augmenting YTHDF2 in wild-type mice impairs memory performance. These findings underscore the pivotal role of YTHDF2-mediated mRNA degradation in regulating learning and memory processes.

Keywords

N6‐methyladenosine; YHTDF2; hippocampus; learning and memory; mRNA degradation; protein synthesis; synaptic transmission.

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