The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury

Table 1

CNS Inhibitors from myelin, proteoglycans, and ECM. This table summarizes the main inhibitors in the CNS originating from myelin, proteoglycans, and ECM. The table includes some of the inhibitory effects of these molecules in the CNS as well as experimental interventions utilized and trialed to counteract the inhibition. This table is by all means not exhaustive but does highlight several influential studies that have demonstrated inhibition in the CNS and/or ways to counteract it.

Molecule	Inhibitory effect	Interventions to counteract inhibition	References
Myelin-associated inhibitors (MAIs)
Myelin-associated glycoprotein (MAG)	Inhibits neurite outgrowth	MAG KO mice	[52, 53, 72–77, 107, 108]
	Induces growth cone retraction	Immunodepletion of MAG
Nogo-A	Inhibits neurite outgrowth; induces growth cone collapse	Anti-Nogo A antibody	[54, 55, 57–66, 78–80, 84–87]
	Restriction of synaptic plasticity and learning/memory		[91, 93, 94, 100, 101, 107, 108, 116–118]
Oligodendrocyte myelin glycoprotein (OMgp)	Inhibits neurite outgrowth	OMgp KO mice	[56, 67–71, 84, 107, 108]
	Inhibits collateral sprouting
MAI Receptors
Nogo-66 receptor 1 (NgR1)	Inhibits neurite outgrowth; induces growth cone collapse	NgR1 KO mice	[61, 62, 68, 80–85, 89, 90, 93, 94]
	Restriction of synaptic plasticity and learning/memory	Blocking NgR1 receptor	[102, 103, 105, 106, 112–114]
Paired immunoglobulin-like receptor B (PirB)	Restriction of ocular dominance plasticity; inhibits neurite	PirB KO mice	[95, 103, 104]
	Outgrowth; induces growth cone collapse	Blocking PirB receptor
Sphingolipid 1-phopsphate receptor 2 (S1PR2)	Inhibits neurite outgrowth; restriction of synaptic plasticity	Blocking S1PR2 receptor	[88]
ECM and glycoproteins
Chondroitin sulfate proteoglycans (CSPGs—brevican, neurocan, aggrecan, phosphacan, versican)	Localized to PNNs; restriction of plasticity through synaptic	ChABC enzyme - removes CS-GAGs of PNNs	[10, 13–15, 113, 142–144, 155]
	Stabilization in mature neurons;	Novel peptide-mimetic of PTPσ receptor	[159–163, 168–177]
	Secreted by reactive astrocytes of glial scar limits remyelination	Xyloside treatment (after demyelination)
Link proteins (Crtl1/Hapln1; Bral2/Hapln4)	Localized to PNNs; restriction of plasticity through synaptic stabilization in mature neurons	Crtl1 conditional KO mice (neurons)	[142, 143, 154]
Hyaluronan	Localized to PNNs; restriction of plasticity through synaptic stabilization in mature neurons	Inhibitor not yet tested in CNS	[142, 143]
Tenascin-R (TN-R)	Localized to PNNs; restriction of plasticity through synaptic stabilization in mature neurons;	TN-R KO mice	[7, 16, 142, 144–146, 155, 182, 183, 186, 187]
Tenascin-C (TN-C)	Creates neuroanatomical boundaries for growth in development secreted by reactive astrocytes after injury	TN-C KO mice	[7, 17–19, 155, 179, 180, 183–185]
		Reexpression of α9β1 receptor
Semaphorins	Axonal guidance/chemorepulsive molecule		[188, 190]
Sema 3A	Localized to PNNs; resticition of plasticity through synaptic stabilization in mature neurons; localized to glial scar postinjury	Sema3A inhibitor (SM-216289)	[147, 189, 191–193]
Sema 3B	Localized to PNNs; restriction of plasticity through synaptic stabilization in mature neurons	Inhibitor not yet tested in CNS	[147]
Sema 4D	Localized to myelinating oligodendrocytes in injury	Inhibitor not yet tested in CNS	[194]