Molecular control of brain plasticity and repair

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Abstract

Recovery of function after damage to the CNS is limited due to the absence of axon regeneration and relatively low levels of plasticity. Plasticity in the CNS can be reactivated in the adult CNS by treatment with chondroitinase ABC, which removes glycosaminoglycan (GAG) chains from chondroitin sulfate proteoglycans (CSPGs). Plasticity in the adult CNS is restricted by perineuronal nets (PNNs) around many neuronal cell bodies and dendrites, which appear at the closure of critical periods and contain several inhibitory CSPGs. Formation of these structures and the turning off of plasticity is triggered by impulse activity in neurons. Expression of a link protein by neurons is the event that triggers the formation of PNNs. Treatment with chondroitinase removes PNNs and other inhibitory influences in the damaged spinal cord and promotes sprouting of new connections. However, promoting plasticity by itself does not necessarily bring back useful behavior; this only happens when useful connections are stabilized and inappropriate connections removed, driven by behavior. Thus after rodent spinal cord injury, combining a daily rehabilitation treatment for skilled paw function with chondroitinase produces much greater recovery than either treatment alone. The rehabilitation must be specific for the behavior that is to be enhanced because non-specific rehabilitation improves locomotor behavior but not skilled paw function. Plasticity-enhancing treatments may therefore open up a window of opportunity for successful rehabilitation.

Section snippets

Mechanisms of recovery after CNS damage

After damage to the CNS, there is loss of function due to structural damage, inflammation, edema, and compression. Edema usually resolves rapidly, but inflammatory processes may continue for weeks, with release of cytokines, nitric oxide, and free radicals leading to conduction failure, demyelination, and other dysfunctions. Eventually, the patient is left with the consequences of structural damage and the loss of function that results from it. There is considerable spontaneous recovery from

Plasticity in recovery of function

The word “plasticity” is used as regards recovery of function in the damaged CNS to mean any process that leads to recreation of functional circuits, excluding long-distance axon regeneration. Short-distance sprouting above and below lesions leading to formation of new connections and alteration in the strength of existing connections are the processes involved. These changes can allow signals to bypass areas of damage through newly created circuits, and can also reassign areas of the CNS to

Plasticity decreases with age

The most studied example of CNS plasticity is the ocular dominance shift that occurs after disadvantaging one eye, leading to the other eye winning more space on the visual cortex. This form of plasticity is developmentally controlled, with a critical period for plasticity after which visual deprivation produces little change in cortical connections (Berardi et al., 2003). Where it has been studied, most other parts of the CNS appear to show similar critical periods, with a peak of plasticity

Methods of restoring plasticity in the adult CNS

It might seem logical that the best methods for reactivating plasticity in the CNS would be to undo the events that lead to the closure of the critical periods. This is not exactly how things have worked out. It has been clear for some time that the ending of the critical period for ocular dominance plasticity is associated with changes in the level of GABAergic inhibition and with the maturation of GABAergic interneurons (Hensch, 2004). Unfortunately, any large systemic blocking of GABAergic

Chondroitinase and CSPGs

Chondroitin sulfate proteoglycans (CSPGs) are upregulated in glial scar tissue and are inhibitory to axon regeneration, mainly through the action of their sulfated glycosaminoglycan (GAG) chains (Galtrey and Fawcett, 2007). CSPGs are generic barrier-forming molecules that guide axons in development and probably act as infection barriers when upregulated in injuries. Bacteria therefore evolved several forms of the enzyme chondroitinase, which digests the GAG chains to disaccharides, in the

NogoA and plasticity

Many of the phenomona described previously for the control of plasticity by CSPGs also apply to NogoA. Thus, animals lacking the Nogo receptor show continuing ocular dominance plasticity into adulthood (McGee et al., 2005). Blocking NogoA with antibodies or interfering with the receptor using peptides or knockdowns can all lead to enhanced sprouting, formation of new connections, and recovery of function after damage (Buchli and Schwab, 2005). Although the effects of NogoA manipulations are

Inosine

Inosine was identified as a factor responsible for the regeneration of fish retinal axons. It is now known to stimulate the activity of the enzyme Mst3b, which is on a neurotrophin signaling pathway in neurons (Irwin et al., 2006). It would therefore be expected to exert its effects by increasing the ability of neurons to grow new processes and overcome inhibitory environments. When given to rats after spinal cord injury, it promotes both axon regeneration and recovery of function (Benowitz et

Promoting plasticity opens a window of opportunity for rehabilitation

High levels of plasticity by themselves would not be expected to have behavioral consequences. Increased rates of sprouting and synapse formation, if they are random, will not be useful to the animal. In order to produce useful behavioral outcomes, the CNS must select useful new connections and remove inappropriate ones. During the later stages of development, there is activity-dependent refinement of exuberant connections in which successful connections are strengthened and inappropriate

Do the treatments that restore plasticity also promote axon regeneration?

The three treatments highlighted previously as promoters of plasticity are also somewhat effective at promoting axon regeneration in the damaged CNS. Some features of plasticity are similar to long-distance axon regeneration, namely, local sprouting of processes, while others such as changes in synaptic strength are different. It is not clear at present which aspects of plasticity are enhanced by chondroitinase, anti-NogoA, and inosine, nor is it known in detail which connections are formed and

How might therapies be combined to treat spinal cord injury?

There are now several treatments that show promise for treating spinal cord injury and other forms of CNS damage. They are divided roughly into five categories: (1) removal of inhibition in the environment, (2) enhancing the intrinsic ability of process growth, (3) providing cellular bridges for axon growth, (4) actions at synapses, and (5) replacing lost neurons and glia. It is logical to think that interventions from the different categories could have additive effects. It is also possible

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