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Novel Object Recognition Test for the Investigation of Learning and Memory in Mice
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m6A facilitates hippocampus-dependent learning and memory through YTHDF1.

Hailing Shi1,2,3,4, Xuliang Zhang5,6, Yi-Lan Weng7,8

  • 1Department of Chemistry, The University of Chicago, Chicago, IL, USA.

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|November 8, 2018
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Summary
This summary is machine-generated.

N6-methyladenosine (m6A) RNA modification, via YTHDF1 protein, promotes neuronal protein synthesis and enhances learning and memory. Deleting Ythdf1 impairs memory and synaptic function in mice.

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Area of Science:

  • Neuroscience
  • Epigenetics
  • Molecular Biology

Background:

  • N6-methyladenosine (m6A) is a prevalent RNA modification in mammals, regulating RNA fate and function.
  • m6A is abundant in the nervous system and influences neural functions.
  • The role of m6A in mRNA translation in vivo, particularly in the brain, is largely unexplored.

Purpose of the Study:

  • To investigate the role of m6A and its binding protein YTHDF1 in mRNA translation in the adult mouse hippocampus.
  • To determine the impact of YTHDF1 on learning, memory, and synaptic plasticity.
  • To elucidate the mechanism by which m6A influences neuronal protein synthesis.

Main Methods:

  • Genetic deletion and re-expression of Ythdf1 in adult mice.
  • Hippocampus-specific acute knockdown of Ythdf1 and Mettl3.
  • Transcriptome-wide mapping of YTHDF1 and m6A sites.
  • Nascent protein labeling and tether reporter assays in hippocampal neurons.

Main Results:

  • YTHDF1 mediates m6A-dependent promotion of protein translation of target mRNAs in response to neuronal stimuli.
  • Ythdf1 knockout mice exhibit learning and memory deficits, impaired synaptic transmission, and long-term potentiation.
  • YTHDF1 enhances protein synthesis in a stimulus-dependent manner in hippocampal neurons.

Conclusions:

  • YTHDF1 facilitates the translation of m6A-modified neuronal mRNAs upon stimulation.
  • This m6A-YTHDF1 pathway is crucial for learning and memory processes in the hippocampus.