Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27462-7
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Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft) [DFG SFB1190/P09, DFG SFB1286/A03, RI 1967/10-1/NeuroNex, RI 1967/7-3, RI 1967/11-1]
- German Ministry for Education and Research [13N15328/NG-FLIM]
- European Research Council (ERC) under the European Union [835102]
- DFG [GRK SynAge 2413/1, 2067/1-390729940]
- Nieders. Vorab [76251-12-6/19/ZN 3458]
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The study reveals that the neuronal extracellular matrix (ECM) can undergo frequent remodeling through endocytosis and recycling of ECM proteins, with key protein Tenascin-R being internalized and resurfacing near synapses. Disrupting the recycling process severely impairs neuronal function, notably reducing synaptic vesicle exo- and endocytosis. The frequent remodeling of neuronal ECM is crucial for maintaining normal neural function.
The brain extracellular matrix (ECM) consists of extremely long-lived proteins that assemble around neurons and synapses, to stabilize them. The ECM is thought to change only rarely, in relation to neuronal plasticity, through ECM proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. Using multiple ECM labeling and imaging assays, from super-resolution optical imaging to nanoscale secondary ion mass spectrometry, both in culture and in brain slices, we find that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within similar to 3 days, in an activity-dependent fashion. Interfering with the recycling process perturbs severely neuronal function, strongly reducing synaptic vesicle exo- and endocytosis. We conclude that the neuronal ECM can be remodeled frequently through mechanisms that involve endocytosis and recycling of ECM proteins.
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