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CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory

Molecular Psychiatry volume 28, pages 2728–2736 (2023)Cite this article

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Abstract

The late 1990s were banner years in molecular neuroscience; seminal studies demonstrated that local protein synthesis, at or near synapses, was necessary for synaptic plasticity, the underlying cellular basis of learning and memory [1, 2]. The newly made proteins were proposed to “tag” the stimulated synapse, distinguishing it from naive synapses, thereby forming a cellular memory [3]. Subsequent studies demonstrated that the transport of mRNAs from soma to dendrite was linked with translational unmasking at synapses upon synaptic stimulation. It soon became apparent that one prevalent mechanism governing these events is cytoplasmic polyadenylation, and that among the proteins that control this process, CPEB, plays a central role in synaptic plasticity, and learning and memory. In vertebrates, CPEB is a family of four proteins, all of which regulate translation in the brain, that have partially overlapping functions, but also have unique characteristics and RNA binding properties that make them control different aspects of higher cognitive function. Biochemical analysis of the vertebrate CPEBs demonstrate them to respond to different signaling pathways whose output leads to specific cellular responses. In addition, the different CPEBs, when their functions go awry, result in pathophysiological phenotypes resembling specific human neurological disorders. In this essay, we review key aspects of the vertebrate CPEB proteins and cytoplasmic polyadenylation within the context of brain function.

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Fig. 1: Illustrations of methods for poly(A) length measurement.
Fig. 2: Model of CPEB-mediated mRNA repression coupled to dendritic localization followed by local activation.

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Funding

This work was supported by National Science and Technology Council [NSTC111-2311-B-001-020-MY3] and Academia Sinica to Y-SH, the FEDER/Spanish Ministry of Science, Innovation and Universities (PID2020-119533 GB-I00 to RM and PID2020-118937RB-I00 to MF), Worldwide Cancer Research Foundation (20_0284), World Cancer Research Fund International (2020_021), La Caixa Foundation (HR18_00302), and La Marató TV3 Foundation (2019_e0259) to RM and MF, and GM046779 and GM135087 to JDR. IRB is the recipient of a Severo Ochoa Award of Excellence from the Spanish Government. IRB and IDIBAPS are supported by the CERCA Program (Catalan Government).

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Author notes

  1. These authors contributed equally: Yi-Shuian Huang, Raul Mendez.

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    Yi-Shuian Huang

  2. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain

    Raul Mendez

  3. Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain

    Raul Mendez

  4. IDIBAPS Biomedical Research Institute, 08036, Barcelona, Spain

    Mercedes Fernandez

  5. Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA

    Joel D. Richter

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  1. Yi-Shuian Huang
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  2. Raul Mendez
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  3. Mercedes Fernandez
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  4. Joel D. Richter
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All authors co-wrote the manuscript and all authors edited the final draft.

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Correspondence to Yi-Shuian Huang, Raul Mendez or Joel D. Richter.

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Huang, YS., Mendez, R., Fernandez, M. et al. CPEB and translational control by cytoplasmic polyadenylation: impact on synaptic plasticity, learning, and memory. Mol Psychiatry 28, 2728–2736 (2023). https://doi.org/10.1038/s41380-023-02088-x

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  • DOI: https://doi.org/10.1038/s41380-023-02088-x

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