Transient dysregulation of extracellular matrix modulates extrasynaptic transmission and can reactivate neuroplasticity in brain diseases

Extracellular space (ECS), the extracellular matrix (ECM), and glia are key players in neurodegeneration, psychiatric disorders, memory maintenance, and brain plasticity. The macromolecular network within the ECS exist in two principal forms - diffuse ECM and perineuronal nets (PNNs) - both of which influence brain development and aging, synaptogenesis, neuroplasticity, the progression of neurodegenerative diseases, and recovery after CNS injury. Inhibition of hyaluronan synthesis disrupts both perineuronal nets (PNNs) and diffuse ECM and reduces the astrocytic and microglia network integrity. These structural alterations lead to an approximate 30% increase in ECS volume, changes in ECS geometry, and altered diffusivity of brain tissue [1]. Together, these findings indicate that ECM disruption facilitates more efficient transport of ions, neurotransmitters and neuroactive substances within the ECS, broadens inter-neuronal communication via extrasynaptic transmission, and enhances efficient clearance of metabolic brain waste products. Associated modifications of tripartite synapses, increased synaptic crosstalk, transmitter spill-over and the formation of new synaptic contacts may augment synaptic plasticity. Targeted manipulation of ECM could be therapeutically exploited to promote plasticity in treatment of brain diseases, to enhance cell migration, axonal growth and support formation of new synaptic connections. Importantly, enlarged ECS and brain diffusivity may also improve efficiency of drug delivery.

[1] Sykova, E. et al. Disruption of Extracellular Matrix and Perineuronal Nets Modulates Extracellular Space Volume and Geometry. J Neurosci 45, doi:10.1523/JNEUROSCI.0517-24.2024 (2025).

Supported by Slovak grant agency grant APVV-23-0436.