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Updated: Jun 4, 2025

Preparation of Tunable Extracellular Matrix Microenvironments to Evaluate Schwann Cell Phenotype Specification
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Disruption of Extracellular Matrix and Perineuronal Nets Modulates Extracellular Space Volume and Geometry.

Eva Syková1, Ivan Voříšek2, Zenon Starčuk3

  • 1Institute of Neuroimmunology, Slovak Academy of Science, Bratislava 84510, Slovakia sykovae@gmail.com.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|January 3, 2025
PubMed
Summary

Disrupting the brain's extracellular matrix (ECM) with 4-methylumbelliferone (4-MU) increased extracellular space (ECS) volume and altered diffusion, impacting neural plasticity and communication.

Keywords:
extracellular diffusionextracellular matrixextracellular transmissionhyaluronan synthaseperineuronal netsplasticity

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • The brain's extracellular matrix (ECM), comprising perineuronal nets (PNNs) and diffuse ECM (dECM), is crucial for neural development, plasticity, and disease progression.
  • ECM remodeling influences extrasynaptic transmission by altering neuroactive substance diffusion within the extracellular space (ECS).

Purpose of the Study:

  • To investigate how disrupted PNNs and dECM affect brain diffusibility.
  • To analyze the impact of hyaluronan (HA) synthesis inhibition on ECM structure and ECS volume.

Main Methods:

  • Oral administration of 4-methylumbelliferone (4-MU), a HA synthesis inhibitor, to rats for up to 6 months.
  • Immunohistochemical staining for ECM components and glial fibrillary acidic protein (GFAP).
  • Real-time iontophoresis and diffusion-weighted magnetic resonance imaging (dMRI) to assess ECS volume and water diffusion.

Main Results:

  • 4-MU treatment downregulated PNNs, HA, chondroitin sulfate proteoglycans, and GFAP, indicating ECM and astrocyte changes.
  • ECS volume fraction (α) in the somatosensory cortex increased by 35% (from 0.20 to 0.27).
  • dMRI revealed decreased mean diffusivity and fractional anisotropy (FA) across multiple brain regions and the spinal cord.

Conclusions:

  • Modulation of PNNs and dECM leads to increased ECS volume and reduced FA.
  • These ECM changes, along with astrocyte atrophy, may affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity.
  • The observed ECM alterations were reversible upon cessation of 4-MU treatment.