Extracellular matrix proteolysis maintains synaptic plasticity during brain development

ABSTRACT: Synapses are highly dynamic during early brain development, enabling the rapid adaptations that occur as neural circuits remodel in response to experience. The extracellular matrix (ECM) has been proposed as a critical regulator of synaptic plasticity in the brain. However, the molecular mechanisms that regulate the ECM and their impact on structural plasticity of synapses during brain development are unknown. Here, using time lapse imaging of excitatory synapses in zebrafish hindbrain motor neurons during development we observed synapses that were both short lived (<6 hours), and longer lived (>24 hours). Loss of ECM via hyaluronidase digestion or genetic deletion of brevican preferentially destabilized short-lived synapses relative to stable synapses, leading to increased synapse density. Conversely, genetic loss of matrix metalloprotease 14 (MMP14) led to accumulation of brevican and stabilized short-lived synapses, resulting in increased synapse density. Zebrafish microglial processes contacted synapses and expressed cell surface MMP14. Microglial MMP14 was required for its effects on synapse numbers and brevican digestion both in zebrafish as well as in triculture from human induced pluripotent stem cells. These pathways also impacted motor habituation in freely swimming fish and were required for stress-induced synapse plasticity. Based on these findings, we propose a model whereby ECM accumulation during development increases the probability that a synapse will convert from dynamic to stable. These studies define a molecular mechanism whereby ECM remodeling by microglia promote synapse plasticity in the developing brain.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Justin McKetney  

LAB HEAD: Danielle Swaney

PROVIDER: PXD060477 | Pride | 2026-03-16

REPOSITORIES: Pride