TY  - JOUR
AU  - Singh, Jeet Bahadur
AU  - Perelló-Amorós, Bartomeu
AU  - Schneeberg, Jenny
AU  - Mirzapourdelavar, Hadi
AU  - Seidenbecher, Constanze I
AU  - Fejtová, Anna
AU  - Dityatev, Alexander
AU  - Frischknecht, Renato
TI  - Activity-dependent extracellular proteolytic cascade cleaves the ECM component brevican to promote structural plasticity.
JO  - EMBO reports
VL  - 27
IS  - 1
SN  - 1469-221X
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2026-00063
SP  - 163 - 185
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Brevican: metabolism
KW  - Extracellular Matrix: metabolism
KW  - Rats
KW  - Neuronal Plasticity
KW  - Long-Term Potentiation
KW  - Proteolysis
KW  - Astrocytes: metabolism
KW  - Hippocampus: metabolism
KW  - Hippocampus: physiology
KW  - Male
KW  - Synapses: metabolism
KW  - Receptors, N-Methyl-D-Aspartate: metabolism
KW  - Neurons: metabolism
KW  - ADAMTS (Other)
KW  - Aggrecan (Other)
KW  - Dendritic Spines (Other)
KW  - Perineuronal Nets (Other)
KW  - Proprotein Convertase (Other)
KW  - Brevican (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41261283
DO  - DOI:10.1038/s44319-025-00644-w
UR  - https://pub.dzne.de/record/283184
ER  -