Molecular control of brain plasticity and repair
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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