The role of proteoglycans in regeneration and plasticity

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are up‐regulated in glial scar tissue and inhibit axon regeneration. Not only are the protein cores up‐regulated, but also there is more glycosaminoglycan (GAG) attached to them. The final stage of GAG synthesis is sulfation, which can occur in three positions. Both 6‐sulfated GAG and the sulfotransferase that sulfates N‐acetylgalactosamine in the 6 position is specifically up‐regulated in glial scar tissue, in inhibitory glial cells and in astrocytes treated with tumour growth factor α (TGF‐α) and TGF‐β. Removal of GAG chains by digestion with chondroitinase or inhibition of GAG synthesis with chlorate or β‐D‐xylosides, removes much of the inhibition from CSPGs in vitro. We therefore tested to see whether GAG digestion by chondroitinase would promote axon regeneration in vivo. We first treated mechanical lesions of the nigrostriatal tract and saw regeneration of about 4% of axons back to their target. Next, dorsal column lesions of the spinal cord at C4 were treated. Both sensory and corticospinal axons regenerated in treated cords, and there was rapid return of function in beam and grid walking tests. The return of function was so rapid that we hypothesized that some of it might be due to enhanced plasticity. Many neuronal cell bodies and dendrites are coated in thick perineuronal nets of inhibitory CSPGs and tenascin‐R, which would certainly be expected to prevent the formation of new synapses. We therefore tested the effects of chondroitinase treatment in a plasticity model: ocular dominance shift in the visual cortex following monocular deprivation. Monocular deprivation in adult animals normally produces no ocular dominance shift. However, in adult animals in which the cortex was treated with chondroitinase, there was a large shift in response to monocular deprivation.