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

Emmanouela Kallergi, Akrivi-Dimitra Daskalaki, Angeliki Kolaxi, Come Camus, Evangelia Ioannou, Valentina Mercaldo, Per Haberkant, Frank Stein, Kyriaki Sidiropoulou, Yannis Dalezios, Mikhail M. Savitski, Claudia Bagni, Daniel Choquet, Eric Hosy and Vassiliki Nikoletopoulou ()
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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
Mikhail M. Savitski: European Molecular Biology Laboratory (EMBL)
Claudia Bagni: University of Lausanne
Daniel Choquet: University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience
Eric Hosy: University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience
Vassiliki Nikoletopoulou: University of Lausanne

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28301-z

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