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Dendritic autophagy degrades postsynaptic proteins and is required for long-term synaptic depression in mice

Author

Listed:
  • Emmanouela Kallergi

    (University of Lausanne)

  • Akrivi-Dimitra Daskalaki

    (University of Lausanne)

  • Angeliki Kolaxi

    (University of Lausanne)

  • Come Camus

    (University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience)

  • Evangelia Ioannou

    (University of Crete)

  • Valentina Mercaldo

    (University of Lausanne)

  • Per Haberkant

    (European Molecular Biology Laboratory (EMBL))

  • Frank Stein

    (European Molecular Biology Laboratory (EMBL))

  • Kyriaki Sidiropoulou

    (University of Crete)

  • Yannis Dalezios

    (University of Crete
    Foundation for Research and Technology—Hellas (FORTH))

  • Mikhail M. Savitski

    (European Molecular Biology Laboratory (EMBL)
    University of Rome Tor Vergata)

  • Claudia Bagni

    (University of Lausanne
    University of Rome Tor Vergata)

  • Daniel Choquet

    (University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience
    University of Bordeaux, CNRS, INSERM, Bordeaux Imaging Center)

  • Eric Hosy

    (University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience)

  • Vassiliki Nikoletopoulou

    (University of Lausanne)

Abstract

The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.

Suggested Citation

  • Emmanouela Kallergi & Akrivi-Dimitra Daskalaki & Angeliki Kolaxi & Come Camus & Evangelia Ioannou & Valentina Mercaldo & Per Haberkant & Frank Stein & Kyriaki Sidiropoulou & Yannis Dalezios & Mikhail , 2022. "Dendritic autophagy degrades postsynaptic proteins and is required for long-term synaptic depression in mice," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28301-z
    DOI: 10.1038/s41467-022-28301-z
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    References listed on IDEAS

    as
    1. Hongmei Shen & Huiwen Zhu & Debabrata Panja & Qinhua Gu & Zheng Li, 2020. "Autophagy controls the induction and developmental decline of NMDAR-LTD through endocytic recycling," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    2. Joseph D. Mancias & Xiaoxu Wang & Steven P. Gygi & J. Wade Harper & Alec C. Kimmelman, 2014. "Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy," Nature, Nature, vol. 509(7498), pages 105-109, May.
    3. Benjamin Compans & Come Camus & Emmanouela Kallergi & Silvia Sposini & Magalie Martineau & Corey Butler & Adel Kechkar & Remco V. Klaassen & Natacha Retailleau & Terrence J. Sejnowski & August B. Smit, 2021. "NMDAR-dependent long-term depression is associated with increased short term plasticity through autophagy mediated loss of PSD-95," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    4. Patrick Lüningschrör & Beyenech Binotti & Benjamin Dombert & Peter Heimann & Angel Perez-Lara & Carsten Slotta & Nadine Thau-Habermann & Cora R. von Collenberg & Franziska Karl & Markus Damme & Arie H, 2017. "Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
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