John van Geest Centre for Brain Repair

School of Clinical Medicine

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Plasticity and recovery from nervous system damage

Plasticity and recovery from nervous system damage

Plasticity is the ability of the nervous system to rewire its connections. Some forms of plasticity are the basis of memory. Other forms enable healthy parts of the nervous system to take over the function of areas that are damaged. The Fawcett Lab is interested in plasticity because it is the main mechanism by which the nervous system recovers from neurological damage. In most parts of the nervous system there is a critical period early in life during which there is a high level of plasticity, but much of this plasticity is lost at around 6 years old in humans. Children younger than this show a much greater ability to compensate for CNS damage than adults. Treatments to restart plasticity in the adult CNS are therefore beneficial in promoting functional recovery after CNS damage. Increased plasticity could be useful in many conditions affecting the nervous system, including spinal cord injury, stroke, head injury and multiple sclerosis.

Our interest in plasticity began following experiments in spinal cord injury in rats in which proteoglycans were digested with chondroitinase. This treatment produced dramatic return of function, much of which was due to an increase in plasticity.

Plasticity and rehabilitation

Reactivating plasticity with chondroitinase leads to sprouting of the axons, and many new connections. However, this by itself does not lead to functional recovery in a difficult task requiring skilled paw use. Animals have to learn to use the new connections through rehabilitation, and rehabilitation is dramatically more successful when the nervous system is rendered plastic.

Perineuronal nets and plasticity

At the end of critical periods many neurons in the CNS develop layers of cartilage-like extracellular matrix around their cell bodies and dendrites, known as perineuronal nets. Degrading the nets with chondroitinase reactivates plasticity. We have been working out how the nets are formed. All neurons with a perineuronal net synthesize the matrix backbone molecule hyaluronan, and also synthesize a link protein which stabilised proteoglycan binding to hyaluronan. Recent work has shown that preventing synthesis of link protein prevents formation of perineuronal nets, and animals without perineuronal nets retain their plasticity as adults. We have developed a method of extracting the perineuronal net glycans, and we find that they have different sulphation patterns to glycans elsewhere in the brain, giving them distinctive binding properties. They bind the inhibitory molecule semaphorin 3 in the CNS, which may be one way in which they affect synapses.

Kwok JC, Yang S, Fawcett JW (2014) Neural ECM in regeneration and rehabilitation. Prog Brain Res 214:179-192.

Vo T, Carulli D, Ehlert EM, Kwok JC, Dick G, Mecollari V, Moloney EB, Neufeld G, De WF, Fawcett JW, Verhaagen J (2013) The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain. Mol Cell Neurosci 56C:186-200.

Orlando c, Ster J, Gerber U, Fawcett JW, Raineteau O (2012) Perisynaptic chondroitin sulfate proteoglycans restrict structural plasticity in an integrin-dependent manner. J Neurosci 32:18009-17, 18017a.

Wang D, Ichiyama RM, Zhao R, Andrews MR, Fawcett JW (2011) Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. J Neurosci 31:9332-9344.

Vorobyov V, Kwok JC, Fawcett JW, Sengpiel F (2013) Effects of digesting chondroitin sulfate proteoglycans on plasticity in cat primary visual cortex. J Neurosci 33:234-243.

Kwok JC, Dick G, Wang D, Fawcett JW (2011) Extracellular matrix and perineuronal nets in CNS repair. Dev Neurobiol.

Carulli, T. Pizzorusso, J. C. Kwok, E. Putignano, A. Poli, S. Forostyak, M. R. Andrews, S. S. Deepa, T. Glant, and J. W. Fawcett. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133:2331-2347, 2010.

Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 2009; 12: 1145-1151.

 

Perineuronal nets, plasticity and Alzheimer’s disease

Memory is a form of plasticity, so we investigated the role of perineuronal nets in memory. Surprisingly, animals lacking perineuronal nets show a massive prolongation of memory. Animals that express a mutant form of the tau protein model many aspects of Alzheimer’s disease, and have a profound memory deficit. We have been able to completely restore memory in these animals by digesting away their perineuronal nets.

Yang S, Cacquevel M, Saksida LM, Bussey TJ, Schneider BL, Aebischer P, Melani R, Pizzorusso T, Fawcett JW, Spillantini MG (2015) Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology. Exp Neurol 265:48-58.

Romberg C, Yang S, Melani R, Andrews MR, Horner AE, Spillantini MG, Bussey TJ, Fawcett JW, Pizzorusso T, Saksida LM (2013) Depletion of Perineuronal Nets Enhances Recognition Memory and Long-Term Depression in the Perirhinal Cortex. J Neurosci 33:7057-7065.

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