# Extracellular matrix proteolysis maintains synapse plasticity during brain development

## TL;DR

This study shows that the brain's extracellular matrix helps control synapse plasticity during development by regulating the stability of new synapses.

## Contribution

The study identifies microglial MMP14 as a key enzyme that digests the ECM to increase plasticity of newborn synapses during brain development.

## Key findings

- Disruption of the ECM destabilizes dynamic synapses and reduces synapse density.
- Loss of MMP14 increases the lifetime of dynamic synapses and boosts overall synapse density.
- MMP14 and brevican are essential for experience-dependent synapse plasticity in a motor learning task.

## Abstract

The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and have been studied predominantly in adulthood. Here, using live imaging of excitatory synapses in zebrafish hindbrain, we observed a bimodal distribution of short-lived (dynamic) and longer-lived (stable) synapses. Disruption of ECM via digestion or brevican deletion destabilized dynamic synapses and led to decreased synapse density. Conversely, loss of matrix metalloproteinase 14 (MMP14) led to accumulation of brevican and increased the lifetime of the dynamic synapse pool without affecting the stable synapse pool, resulting in increased overall synapse density. Microglial MMP14 was essential to these effects in both fish and human induced pluripotent stem cell-derived cultures. Both MMP14 and brevican were required for experience-dependent synapse plasticity in a motor learning assay. These data, complemented by mathematical modeling, define an essential role of ECM remodeling in maintaining a dynamic subset of synapses during brain development.

This study demonstrates that the extracellular matrix (ECM) of the developing brain stabilizes recently born synapses. The authors identify a microglial metalloprotease that digests the ECM to increase the plasticity of these newborn synapses.