A perineuronal net (PNN) is a layer of lattice-like matrix which enwraps the surface of the soma and dendrites, and in some cases the axon initial segments, in sub-populations of neurons in the central nervous system (CNS). First reported by Camillo Golgi more than a century ago, the molecular structure and the potential role of this matrix have only been unraveled in the last few decades. PNNs are mainly composed of hyaluronan, chondroitin sulfate proteoglycans, link proteins, and tenascin R. The interactions between these molecules allow the formation of a stable pericellular complex surrounding synapses on the neuronal surface. PNNs appear late in development co-incident with the closure of critical periods for plasticity. They play a direct role in the control of CNS plasticity, and their removal is one way in which plasticity can be re-activated in the adult CNS. In this review, we examine the molecular components and formation of PNNs, their role in maturation and synaptic plasticity after CNS injury, and the possible mechanisms of PNN action.
Perineuronal nets (PNNs) are reticular structures that surround the cell body of many neurones, and extend along their dendrites. They are considered to be a specialized extracellular matrix in the central nervous system (CNS). PNN formation is first detected relatively late in development, as the mature synaptic circuitry of the CNS is established and stabilized. Its unique distribution in different CNS regions, the timing of its establishment, and the changes it undergoes after injury all point toward diverse and important functions that it may be performing. The involvement of PNNs in neuronal plasticity has been extensively studied over recent years, with developmental, behavioural, and functional correlations. In this review, we will first briefly detail the structure and organization of PNNs, before focusing our discussion on their unique roles in neuronal development and plasticity. The PNN is an important regulator of CNS plasticity, both during development and into adulthood. Production of critical PNN components is often triggered by appropriate sensory experiences during early postnatal development. PNN deposition around neurones helps to stabilize the established neuronal connections, and to restrict the plastic changes due to future experiences within the CNS. Disruption of PNNs can reactivate plasticity in many CNSs, allowing activity-dependent changes to once again modify neuronal connections. The mechanisms through which PNNs restrict CNS plasticity remain unclear, although recent advances promise to shed additional light on this important subject.
Chondroitinase ABC (ChABC) in combination with rehabilitation has been shown to promote functional recovery in acute spinal cord injury. For clinical use, the optimal treatment window is concurrent with the beginning of rehabilitation, usually 2-4 weeks after injury. We show that ChABC is effective when given 4 weeks after injury combined with rehabilitation. After C4 dorsal spinal cord injury, rats received no treatment for 4 weeks. They then received either ChABC or penicillinase control treatment followed by hour-long daily rehabilitation specific for skilled paw reaching. Animals that received both ChABC and task-specific rehabilitation showed the greatest recovery in skilled paw reaching, approaching similar levels to animals that were treated at the time of injury. There was also a modest increase in skilled paw reaching ability in animals receiving task-specific rehabilitation alone. Animals treated with ChABC and taskspecific rehabilitation also showed improvement in ladder and beam walking. ChABC increased sprouting of the corticospinal tract, and these sprouts had more vGlut1 ϩve presynaptic boutons than controls. Animals that received rehabilitation showed an increase in perineuronal net number and staining intensity. Our results indicate that ChABC treatment opens a window of opportunity in chronic spinal cord lesions, allowing rehabilitation to improve functional recovery.
Anti-Nogo-A antibody and chondroitinase ABC (ChABC) enzyme are two promising treatments that promote functional recovery after spinal cord injury (SCI). Treatment with them has encouraged axon regeneration, sprouting and functional recovery in a variety of spinal cord and central nervous system injury models. The two compounds work, in part, through different mechanisms, so it is possible that their effects will be additive. In this study, we used a rat cervical partial SCI model to explore the effectiveness of a combination of anti-Nogo-A, ChABC, and rehabilitation. We found that spontaneous recovery of forelimb functions reflects the extent of the lesion on the ipsilateral side. We applied a combination treatment with acutely applied anti-Nogo-A antibody followed by delayed ChABC treatment starting at 3 weeks after injury, and rehabilitation starting at 4 weeks, to accommodate the requirement that anti-Nogo-A be applied acutely, and that rehabilitation be given after the cessation of anti-Nogo-A treatment. We found that single treatment with either anti-Nogo-A or ChABC, combined with rehabilitation, produced functional recovery of similar magnitude. The combination treatment, however, was more effective. Both single treatments produced increases in sprouting and axon regeneration, but the combination treatment produced greater increases. Anti-Nogo-A stimulated growth of a greater number of axons with a diameter of > 3 μm, whereas ChABC treatment stimulated increased growth of finer axons with varicosities. These results point to different functions of Nogo-A and chondroitin sulfate proteoglycans in axonal regeneration. The combination of anti-Nogo-A, ChABC and rehabilitation shows promise for enhancing functional recovery after SCI.
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