Extracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R

Abstract

The brain extracellular matrix (ECM) consists of extremely long-lived proteins that assemble around neurons and synapses, to stabilize them. The ECM is thought to change only rarely, in relation to neuronal plasticity, through ECM proteolysis and renewed protein synthesis. We report here an alternative ECM remodeling mechanism, based on the recycling of ECM molecules. Using multiple ECM labeling and imaging assays, from super-resolution optical imaging to nanoscale secondary ion mass spectrometry, both in culture and in brain slices, we find that a key ECM protein, Tenascin-R, is frequently endocytosed, and later resurfaces, preferentially near synapses. The TNR molecules complete this cycle within ~3 days, in an activity-dependent fashion. Interfering with the recycling process perturbs severely neuronal function, strongly reducing synaptic vesicle exo- and endocytosis. We conclude that the neuronal ECM can be remodeled frequently through mechanisms that involve endocytosis and recycling of ECM proteins.

The Synaptic Extracellular Matrix: Long-Lived, Stable, and Still Remarkably Dynamic

“…Considering that it appears to be largely synaptic and tightly linked to local activity, it is possible to imagine that this mechanism is intimately involved in synaptic function. In agreement with this claim, it was shown that perturbing TNR recycling with large antibody aggregates interfered severely with synaptic vesicle release and resulted in structural changes to the postsynapse (Dankovich et al, 2021). We predict that such perturbations to ECM recycling would also have implications for synaptic plasticity, both at the structural and the molecular level, and may also manifest in brain disorders.…”

“…A novel mechanism of ECM remodeling was presented in a recent study by Dankovich and colleagues, based on the recycling of ECM molecules at the synapse. The authors proposed that these molecules are constitutively internalized into neurons, and subsequently resurface and re-integrate into the ECM around synapses (Dankovich et al, 2021 ). A complete recycling loop was described for the glycoprotein TNR, which spans ~3 days ( Figure 3 ).…”

“…In the plot, lines represent the means, shaded areas represent the SEM, and dots represent individual experiments. Adapted from Dankovich et al ( 2021 ) with permission from Springer Nature (http://creativecommons.org/licenses/by/4.0/).…”

“…The data shown in the plots represent the means (long horizontal lines) ± SEM (short horizontal lines), with individual dots indicating separate experiments. Adapted from Dankovich et al ( 2021 ) with permission from Springer Nature (http://creativecommons.org/licenses/by/4.0/).…”

“…In light of these observations, one would expect a mechanism to be in place for maintaining sufficient flexibility of the ECM at synapses, to allow for ongoing structural plasticity. In this review, we discuss a novel mechanism proposed to provide such flexibility, in the form of molecular recycling of ECM components at synapses (Dankovich et al, 2021 ). We begin by briefly reviewing the various roles of ECM components at the tetrapartite synapse and the existing model for ECM remodeling, followed by a discussion on the plausibility of ECM recycling and its potential implications for our current understanding of synaptic signaling.…”