Abstract
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.
Highlights
Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; excessive proteolytic activity is detrimental to the cells
We previously showed that activity of exogenously applied autoactivating mutant of matrix metalloproteinases (MMPs)-9, aaMMP-9 provoked the elongation of dendritic spines[23]
We first investigated whether the elongated morphology of dendritic spines that is caused by MMP-9 activity can be affected by inhibiting the enzyme
Summary
Activity-dependent proteolysis at a synapse has been recognized as a pivotal factor in controlling dynamic changes in dendritic spine shape and function; excessive proteolytic activity is detrimental to the cells. A good example might be provided by extracellular matrix metalloproteinases (MMPs) They are tightly regulated at the levels of gene transcription, mRNA stability, local delivery and translation and the proteins are produced in a latent form, released from the cells to unleash their enzymatic activities only after the propeptide is cleaved off 2. MMP-9, a major metalloproteinase expressed in the brain, was shown to have an important role for physiological synaptic plasticity, i.e., the ability of the adult brain to modify synaptic strength and remodel neuronal circuits underlying learning and memory, by controlling the shape and efficacy of excitatory synapses in the brain[9,10,11,12,13,14]. Whereas Michaluk et al.[23], Tian et al.[20] and Bilousova et al.[24] have shown that excessive MMP-9 activity nencki.gov.pl) www.nature.com/scientificreports/
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