Journal Article

DZNE-2026-00063

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activity-dependent extracellular proteolytic cascade cleaves the ECM component brevican to promote structural plasticity.

Singh, J. B. ; Perelló-Amorós, B. ; Schneeberg, J.DZNE* ; Mirzapourdelavar, H.DZNE* ; Seidenbecher, C. I. ; Fejtová, A. ; Dityatev, A.DZNE* ; Frischknecht, R.

2026
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44319-025-00644-w

Abstract: The brain's perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how activity-induced synaptic plasticity is achieved in the adult brain with a dense ECM is unclear. We hypothesized that neuronal activity induces cleavage of ECM, creating conditions for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical ECM proteoglycan, and the importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings reveal that chemical long-term potentiation (cLTP) triggers rapid brevican cleavage in perisynaptic regions through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process requires NMDA receptor activation and involves astrocytes. Interfering with cLTP-induced brevican cleavage prevents the formation of new dendritic protrusions in CA1 but does not impact LTP induction by theta-burst stimulation of CA3-CA1 synapses. Our data reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.

Keyword(s): Animals (MeSH) ; Brevican: metabolism (MeSH) ; Extracellular Matrix: metabolism (MeSH) ; Rats (MeSH) ; Neuronal Plasticity (MeSH) ; Long-Term Potentiation (MeSH) ; Proteolysis (MeSH) ; Astrocytes: metabolism (MeSH) ; Hippocampus: metabolism (MeSH) ; Hippocampus: physiology (MeSH) ; Male (MeSH) ; Synapses: metabolism (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; ADAMTS ; Aggrecan ; Dendritic Spines ; Perineuronal Nets ; Proprotein Convertase ; Brevican ; Receptors, N-Methyl-D-Aspartate

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Contributing Institute(s):

1. Molecular Neuroplasticity (AG Dityatev)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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