Abstract

Recovery of function in the damaged adult CNS is limited due to the absence of axon regeneration and relatively low levels of plasticity. Both axon regeneration and plasticity are inhibited by molecules and structures in the extracellular matrix. The role of chondroitin sulphate proteoglycans (CSPGs) in the extracellular matrix in the control of plasticity was revealed because chondroitinase, which degrades the glycosaminoglycans (GAGs), promotes recovery of function in the damaged CNS . This recovery of function has now been demonstrated in spinal injury and peripheral nerve repair models. The formation of new circuits is controlled both by levels of plasticity and by behaviour. We have therefore examined the interaction of rehabilitation and plasticity, based on skilled forelimb function. A rehabilitation task for skilled forelimb use combined with chondroitinase produces a dramatic increase in recovery compared to rehabilitation or chondroitinase alone. Plasticity in the adult CNS may be restricted by perineuronal nets (PNNs) around may neuronal cell bodies and dendrites. These contain inhibitory CSP Gs, hyaluronan, link protein and tenascin R. The components of PNNs are produced either by the neurones themselves or by surrounding glial cells. All neurones with PNNs express both a hyaluronan synthase enzyme and a link protein, and these are probably the key components that trigger the formation of the structures. A link protein knockout animal lacks normal PNNs on its dendrites. The GAGs within PNNs have a different sulphation pattern to those in the general CNS matrix, giving them high affinity for binding molecules which may affect plastic behaviour in neurons. This may be a mechanism that concentrates active molecules in the regions of synapses. In addition to inhibition by inhibitory molecules in myelin and CSP Gs in glial scar tissue, CNS axons have a low intrinsic ability to regenerate. Part of this low regenerative ability can be explained by the fact that CNS axons lack the integrins needed to interact with the matrix of the damaged CNS . The presence of protein translational mechanisms in PNS but not CNS axons is also a factor. Changes in gangliosides are also an important event in regeneration, and these may also differ in the CNS .