4-methylumbelliferone enhances neuroplasticity in the central nervous system: potential oral treatment for SCI

Abstract

Perineuronal nets (PNNs) are specialised extracellular matrix (ECM) structures that act as key plasticity regulators to the central nervous system. Removal of PNNs using chondroitinase ABC injections restores plasticity, however, there are limitations to its application to due to its enzymatic nature. Here, we explore the use of a small molecule 4-methylumbelliferone (4-MU) as an alternative non-invasive strategy to reversibly remove PNNs and enhance plasticity. Oral administration of 4-MU for 10 days successfully and dynamically removed PNNs in vitro. While 4-MU, preferentially downregulated hyaluronan in the spinal cord, a down-regulation of chondroitin sulphate proteoglycans is also observed in the cortex. Long term administration for 8-weeks administration revealed a partial removal of PNNs, and that injury-induced mechanisms promoting cortical structural plasticity are linked to endogenous modulation of ECM molecules. 4-MU is a new tool to unravel the limits of normal and pathological PNN-mediated plasticity.