Transient ECM protease activity promotes synaptic plasticity

• Published in: Scientific reports 2016-06, Vol.6 (1), p.27757-27757, Article 27757
• Main Authors: Magnowska, Marta, Gorkiewicz, Tomasz, Suska, Anna, Wawrzyniak, Marcin, Rutkowska-Wlodarczyk, Izabela, Kaczmarek, Leszek, Wlodarczyk, Jakub
• Format: Article
• Language: English
• Subjects: 13/109; 14; 14/19; 14/35; 631/378/1595/1554; 631/378/2591/2592; 631/378/340; 82; 96; Animals; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Excitatory Postsynaptic Potentials - drug effects; Extracellular Matrix - metabolism; Hippocampus - drug effects; Hippocampus - physiology; Humanities and Social Sciences; Humans; Long-Term Potentiation - drug effects; Male; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Models, Biological; Morphology; multidisciplinary; Neuronal Plasticity - drug effects; Peptide Hydrolases - metabolism; Physiology; Plasticity; Proteolysis - drug effects; Rats, Transgenic; Receptors, N-Methyl-D-Aspartate - metabolism; Recombinant Proteins - metabolism; Science; Synapses - drug effects; Synapses - metabolism; Time Factors; Tissue Inhibitor of Metalloproteinase-1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep27757

Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; however, excessive proteolytic activity is detrimental to the cells. The exact mechanism of control of these seemingly contradictory outcomes of protease activity remains unknown. Here, we reveal that dendritic spine maturation is strictly controlled by the proteolytic activity and its inhibition by the endogenous inhibitor (Tissue inhibitor of matrix metalloproteinases-1 – TIMP-1). Excessive proteolytic activity impairs long-term potentiation of the synaptic efficacy (LTP) and this impairment could be rescued by inhibition of protease activity. Moreover LTP is altered persistently when the ability of TIMP-1 to inhibit protease activity is abrogated, further demonstrating the role of such inhibition in the promotion of synaptic plasticity under well-defined conditions. We also show that dendritic spine maturation involves an intermediate formation of elongated spines, followed by their conversion into mushroom shape. The formation of mushroom-shaped spines is accompanied by increase in AMPA/NMDA ratio of glutamate receptors. Altogether, our results identify inhibition of protease activity as a critical regulatory mechanism for dendritic spines maturation.