Role of Chondroitin Sulfate Proteoglycans in Axonal Conduction in Mammalian Spinal Cord

Abstract

Chronic unilateral hemisection (HX) of the adult rat spinal cord diminishes conduction through intact fibers in the ventrolateral funiculus (VLF) contralateral to HX. This is associated with a partial loss of myelination from fibers in the VLF (Arvanian et al., 2009). Here, we again measured conduction through the VLF using electrical stimulation while recording the resulting volley and synaptic potentials in target motoneurons. We found that intraspinal injection of chondroitinase-ABC, known to digest chondroitin sulfate proteoglycans (CSPGs), prevented the decline of axonal conduction through intact VLF fibers across from chronic T10 HX. Chondroitinase treatment was also associated with behavior suggestive of an improvement of locomotor function after chronic HX. To further study the role of CSPGs in axonal conduction, we injected three purified CSPGs, NG2 and neurocan, which increase in the vicinity of a spinal injury, and aggrecan, which decreases, into the lateral column of the uninjured cord at T10 in separate experiments. Intraspinal injection of NG2 acutely depressed axonal conduction through the injected region in a dose-dependent manner. Similar injections of saline, aggrecan, or neurocan had no significant effect. Immunofluorescence staining experiments revealed the presence of endogenous and exogenous NG2 at some nodes of Ranvier. These results identify a novel acute action of CSPGs on axonal conduction in the spinal cord and suggest that antagonism of proteoglycans reverses or prevents the decline of axonal conduction, in addition to stimulating axonal growth.

Chondroitinase ABC Combined with Neurotrophin NT-3 Secretion and NR2D Expression Promotes Axonal Plasticity and Functional Recovery in Rats with Lateral Hemisection of the Spinal Cord

“…Short latency, steep rising phase and negligible fluctuation in both latency and amplitude suggested that these responses were most probably monosynaptic, as previously discussed (Arvanian et al, 2009). Previous work indicates these connections are glutamatergic (Hunanyan et al, 2010(Hunanyan et al, , 2011. In the same animals, subsequent stimulation of the right lateral white matter at T6 gave rise to a long latency polyphasic EPSPs with a less steep rising phase in the same left L5 motoneurons, which were variable in shape and peak deflection ( Fig.…”

“…The animals were deeply anesthetized and the spinal cords were exposed. L5 motoneurons were impaled with a sharp glass micropipette electrode and a tungsten sharp electrode was introduced at a depth of 1.3 mm, first in the right and then in the left LWM at T6 to stimulate descending spinal axons, as in previous experiments (Arvanian et al, 2009;Hunanyan et al, 2010).…”

“…The injections were done over a period of 10 min using a glass micropipette (30 m diameter) attached to a Hamilton syringe. This procedure was previously shown to reduce conduction block in fibers contralateral to chronic Hx (Hunanyan et al, 2010). Our earlier studies demonstrated CSPG digestion after similar chondroitinase injection, which was assessed immunohistochemically using the 1-B-5 antibody (which recognizes the sugar stub remaining on CSPG molecules after digestion of the glycosaminoglycan chains) (described in detail in our previous studies: García-Alías et al, 2008.…”

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…This suggests that chABC may modulate immune/inflammatory responses, liberate extracellular matrix-bound facilitatory factors, and overcome interactions between inhibitory CSPGs and extracellular matrix molecules in the injured CNS (reviewed in Crespo et al [85], Bradbury and Carter [86]). Attenuating the decline in axonal conduction through the SCI site could be involved [87]. Additionally, chABC may reduce growth inhibitory responses in neurons and provide neuroprotection by digesting chondroitin sulfate glycosaminoglycan chains that mediate the interaction between CSPGs and the neuron transmembrane receptor protein tyrosine phosphatase sigma [88,89].…”

Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex

“…Initially, it was recognized that CSPGs inhibit axonal sprouting as they are one of the main obstacles to axon regeneration [16][17][18] . It is now clear that the action of CSPG is multifaceted, as an inhibitory effect of CSPGs on axonal conduction and synaptic transmission in adult rat spinal cord has been recently reported 19 .…”