Disruption of Extracellular Matrix and Perineuronal Nets Modulates Extracellular Space Volume and Geometry

The Journal of Neuroscience, 2025 · DOI: https://doi.org/10.1523/JNEUROSCI.0517-24.2024 · Published: February 19, 2025

Simple Explanation

This study explores how breaking down the brain's support structure, specifically perineuronal nets (PNNs) and diffuse extracellular matrix (dECM), affects how substances move around in the brain. Rats were given a substance called 4-MU, which is known to interfere with the production of hyaluronan, a key component of these support structures. The researchers then looked at changes in the brain's structure and how it affected the space between cells. The study found that disrupting these support structures led to an increase in the space between brain cells, which could allow for better communication between neurons. This disruption and increase can lead to increased synaptic plasticity.

Study Duration

2, 4, and 6 months

Participants

52 female Wistar rats

Evidence Level

Not specified

Key Findings

1
Oral treatment with 4-methylumbelliferone (4-MU) downregulated PNNs, HA, chondroitin sulfate proteoglycans, and glial fibrillary acidic protein.
2
Dysregulation of ECM resulted in increased ECS volume fraction α in the somatosensory cortex by 35%.
3
Diffusion-weighted magnetic resonance imaging revealed a decrease of mean diffusivity and fractional anisotropy (FA) in the cortex, hippocampus, thalamus, pallidum, and spinal cord.

Research Summary

This study investigates the effects of disrupting perineuronal nets (PNNs) and diffuse extracellular matrix (dECM) on brain diffusibility using 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan (HA) synthesis, in rats. The results showed that 4-MU treatment leads to a downregulation of ECM components, atrophy of astrocytes, and an increase in the extracellular space (ECS) volume in the somatosensory cortex. These changes in ECM and ECS volume could potentially affect extrasynaptic transmission, cell-to-cell communication, and neural plasticity in the brain and spinal cord.

Practical Implications

Enhanced Extrasynaptic Transmission

Disruption of ECM allows for more efficient transport of ions, neurotransmitters, and neuroactive substances in the ECS.

Increased Synaptic Plasticity

Disruption of PNNs and an increase in ECS volume can result in enhanced cross talk between synapses, spillover of transmitters, and formation of new synaptic contacts.

Potential Therapeutic Target

Manipulation of PNNs and dECM and changes in ECS volume and geometry might be beneficial during treatment of brain diseases by opening plasticity, facilitating cell migration, growth of axons, and formation of new synaptic connections in adulthood.

Study Limitations

1
The study used only female Wistar rats, which may limit the generalizability of the findings to other populations.
2
The study did not directly assess the functional consequences of the observed changes in ECS volume and diffusion parameters on behavior or cognitive performance.
3
The sensitivity of fitting the macromolecular background to global parameters of the fitting algorithm urges some caution.

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