Activation of a hippocampal CREB-pCREB-miRNA-MEF2 axis modulates individual variation of spatial learning and memory capability

I-Fang Wang; Yihan Wang; Yi-Hua Yang; Guo-Jen Huang; Kuen-Jer Tsai; Che-Kun James Shen

doi:10.1016/j.celrep.2021.109477

Activation of a hippocampal CREB-pCREB-miRNA-MEF2 axis modulates individual variation of spatial learning and memory capability

Cell Rep. 2021 Aug 3;36(5):109477. doi: 10.1016/j.celrep.2021.109477.

Authors

I-Fang Wang¹, Yihan Wang², Yi-Hua Yang³, Guo-Jen Huang⁴, Kuen-Jer Tsai⁵, Che-Kun James Shen⁶

Affiliations

¹ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
² Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
³ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.
⁴ Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou 33302, Taiwan.
⁵ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan; Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan. Electronic address: kjtsai@mail.ncku.edu.tw.
⁶ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. Electronic address: ckshen@tmu.edu.tw.

PMID: 34348143
DOI: 10.1016/j.celrep.2021.109477

Abstract

Phenotypic variation is a fundamental prerequisite for cell and organism evolution by natural selection. Whereas the role of stochastic gene expression in phenotypic diversity of genetically identical cells is well studied, not much is known regarding the relationship between stochastic gene expression and individual behavioral variation in animals. We demonstrate that a specific miRNA (miR-466f-3p) is upregulated in the hippocampus of a portion of individual inbred mice upon a Morris water maze task. Significantly, miR-466f-3p positively regulates the neuron morphology, function and spatial learning, and memory capability of mice. Mechanistically, miR-466f-3p represses translation of MEF2A, a negative regulator of learning/memory. Finally, we show that varied upregulation of hippocampal miR-466f-3p results from randomized phosphorylation of hippocampal cyclic AMP (cAMP)-response element binding (CREB) in individuals. This finding of modulation of spatial learning and memory via a randomized hippocampal signaling axis upon neuronal stimulation represents a demonstration of how variation in tissue gene expression lead to varied animal behavior.

Keywords: MEF2; hippocampal miRNAs; individual variation; phospho-CREB; spatial learning and memory.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cyclic AMP Response Element-Binding Protein / metabolism*
Dendritic Spines / metabolism
Excitatory Postsynaptic Potentials
Gene Expression Regulation
HEK293 Cells
Hippocampus / metabolism*
Humans
Long-Term Potentiation
MEF2 Transcription Factors / metabolism
Male
Maze Learning
Memory / physiology*
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Neuronal Outgrowth / genetics
Neuronal Plasticity / genetics
Phosphorylation
Protein Biosynthesis
Spatial Learning / physiology*
Stochastic Processes
Transcription, Genetic
Up-Regulation / genetics

Substances

Cyclic AMP Response Element-Binding Protein
MEF2 Transcription Factors
Mef2a protein, mouse
MicroRNAs
Mirn466 microRNA, mouse