Transient ECM protease activity promotes synaptic plasticity

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.

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…1). In rats, transient proteolytic activity in the synaptomatrix accompanies long-term potentiation and dendrite maturation (Magnowska et al, 2016), which corroborates our model that Timp dynamically restricts synaptic modulation through localized ECM proteolysis. Crucially, pharmacologically balancing Mmp activity in timp null mutants with minocycline treatment restores BMP trans-synaptic signaling (Fig.…”

Synaptic Remodeling Depends on Signaling between Serotonin Receptors and the Extracellular Matrix

“…The functional importance of 5-HT7R/MMP-9-mediated processing of CD44 was further supported by the fact that treatment of hippocampal slices with 5-CT resulted in MMP-9-dependent accumulation of 55-kDa cleavage products of CD44, which was accompanied by impaired LTP impairment in the Schaffer collateral synapses (Figure 7). Previous studies revealed that MMP-9 inhibitors impair the late phase of CA1 LTP but have no effects 60 min after induction of LTP (Nagy et al, 2006), whereas this phase of LTP is impaired in MMP-9-overexpressing rats (Magnowska et al, 2016). In line with these data, MMP-9 inhibitor I did not affect CA1 LTP 60 min after induction of LTP but rescued the defect in LTP induced by 5-CT (Figure 7), supporting the view that stimulation of the 5-HT7R activates MMP-9 and that hyperactivity of MMP-9 impairs LTP.…”

3dSpAn: An interactive software for 3D segmentation and analysis of dendritic spines

“…Images of dendrites in different brain regions were acquired under 561 nm fluorescent illumination using a confocal microscope (63 objective, 1.4 NA) at a pixel resolution of 1024 × 1024 with a 3.43 zoom, resulting in a 0.07µm pixel size [24].…”

“…Refer [24,25] Refer [24,26] Refer [27,28,29,30] Aparatus Figure 1(c) with color transition from red to green describing the spine membership and dendrite membership value of a pixels(above). The block interactive module show the intensity thresholds ths(40) and th d (240) for the spine and dendrite respectively and the graph shows fuzzy membership curve for both spine(red) and dendrite(green).…”