Role of chondroitin sulfate proteoglycans (CSPGs) in synaptic plasticity and neurotransmission in mammalian spinal cord

Chronic unilateral hemisection (HX) of the adult rat spinal cord diminishes conduction through intact fibers in the ventrolateral funiculus (VLF) contralateral to HX. Intraspinal injections of Chondroitinase-ABC, known to digest chondroitin sulfate proteoglycans (CSPGs) in the vicinity of injury, prevented this decline of axonal conduction. This was associated with improved locomotor function. We further injected three purified CSPGs into the lateral column of the uninjured cord at T10: NG2 and neurocan, which increase in the vicinity of a spinal injury, and aggrecan, which decreases. Intraspinal injection of NG2 acutely depressed axonal conduction through the injection region in a dose dependent manner. Similar injections of saline, aggrecan, or neurocan had no significant effect. These results identify a novel acute action of CSPGs on axonal conduction in spinal cord, and suggest that antagonism of proteoglycans reverses or prevents the decline of axonal conduction, in addition to stimulating axonal growth. 3 The accumulation of chondroitin sulfate proteoglycans (CSPGs) in and around the glialscar is a major obstacle for recovery after spinal cord injury (SCI) (1, 2). CSPGs consist of a core protein to which is attached one or more chondroitin sulfate glycosaminoglycan side-chains. CSPGs are involved in a variety of CNS functions, including the modulation of cell adhesion, cell migration, axonal outgrowth and synapse formation (3-7). CSPGs are found diffusely in the extracellular matrix throughout the CNS in the undamaged adult CNS, but also in a condensed matrix around neurons as perineuronal nets and in similar structures at nodes of Ranvier (8, 9). The accumulation of CSPGs in and around injury sites, particularly during the acute phase of injury, is thought to be a major barrier for axonal regeneration in the adult mammalian spinal cord and thus recovery of function after SCI (10-12). Degrading CSPGs by enzymatic removal of chondroitin sulfate chains with the the chondroitin sulphate glycosaminoglycan digensting bacterial enzyme chondroitinase-ABC (Ch'ase) promotes axonal regeneration and stimulates anatomical plasticity in the damaged and undamaged brain and spinal cord and encourages functional recovery (9, 13-17). Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation (18). Many patients with partial spinal cord injuries and preserved axons may nevertheless have no descending motor or ascending sensory function below the injury, and various factors including demyelination and inflammation have been proposed to explain the lack of conduction in surviving axons (19). Recently we found that a lateral hemisection lesion (HX) of the adult rat …