More about inhibitors - beyond the glia scar

One poster presentation at the Society for Neuroscience meeting really caught my eye today, but we need a bit of background first. There are many inhibitors in the central nervous system (CNS) that prevent axonal regeneration after injury. Their function in healthy cord is likely to be related to preventing uncontrolled growth of fibres once the CNS matures after early development and the various circuits are functionally defined. But in the injury state this becomes a problem as we want to create new functional circuits. We’ve talked about myelin – the insulating material surrounding axons – before as one source of inhibition, but another very potent inhibitor comes in the form of an extracellular matrix. This matrix is produced by cells in the CNS and is composed of many different proteins that are covered in side chains. These side chains are responsible for the inhibition and presumably dock with receptors on growing axons signalling them to stop growing. Collectively they’re called CSPGs (chondroitin sulphate proteoglycans).

If this wasn’t bad enough, when the cord is injured the amount of CSPGs dramatically increases at the injury site (forming scar tissue) but also in regions at some distance from the injury site.

Overcoming the inhibitory scar is an important therapeutic target for which we have a potential treatment. The bacterial enzyme, chondroitinase, digests the CSPG side chains leaving them inactive as inhibitors and a great deal of evidence is now available that treatment with chondroitinase is beneficial in terms of improvements in function. Closer investigation of the mechanisms by which chondroitinase may be beneficial suggest that it may not only work by breaking down scar, as originally thought, but it may have other activities, such as increasing plasticity and neuroprotection.

So, what about this poster (programme#365.4)? Well according to Hunanyan (Stony Brook University, NY), after an injury to one side of the spinal cord there is an increase in CSPGs in regions of intact fibres on the other. What’s more, if you look at the signal conduction of these intact fibres you begin to see a decline in activity during the same period of increased CSPGs. The question is, are the two related, because obviously if previously undamaged nervous tissue begins to lose function after injury then preventing this could be important to retaining function.

Hunanyan and colleagues wanted to test whether it was the CSPGs that were causing the decline in activity. They knew adding chondroitinase to the cord after injury would breakdown the CSPGs and if they guessed right, they would see increased activity when they did this, which they did. So, CSPGs appeared to be culprit. But there is more than one type of CSPG and to cut a long story short, they added each individually, looked at activity and found just one was responsible – NG2 ……. but that’s a developing story.

So, chondroitinase may have yet another beneficial effect in addition to breaking down scar tissue, increasing plasticity and neuroprotection; it may also help to maintain good electrical activity in surviving neurons.