Introduction: Neuronal Nogo-66 receptor 1 (NgR1) has attracted attention as a converging point for mediating the effects of myelin-associate inhibitory ligands in the CNS, establishing the growth restrictive environment, and limiting axon regeneration following traumatic injury. However, the importance of NgR1 has been undermined by several studies that have shown the lack of substantial axon regeneration following spinal cord injury (SCI) in NgR1 knockout or knockdown animal models.

Methods: To investigate the factors that may be contributing to the discrepancy, we used mice carrying either a homozygous or heterozygous null mutation in the NgR1 gene and subjected them to either a moderate or severe SCI.

Results: Locomotor function assessments revealed that the level of functional recovery is affected by the degree of injury suffered. Tract tracing of the corticospinal (CST) tract fibers revealed that NgR1 ablation enhanced local collateral sprouting in the mutant mice. Reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs) are upregulated surrounding the injury site. MMP-9, which has been shown to degrade CSPGs, was significantly upregulated in the homozygous mutant mice compared to the heterozygous or wild-type mice. However, CSPG levels remained higher in the homozygous compared to the heterozygous mice, suggesting that the CSPG-degrading activity of MMP-9 may require the presence of NgR1.

Conclusions: Together, these results suggest that NgR1 has important physiological functions, which may have been masked by redundant pathways or confounding factors in previous studies. Therapeutic strategies based on NgR1 antagonism, in combination with other treatment approaches, can have functionally important outcomes for patients suffering from SCI.

Patient Care: 1. There is a need to identify methods of treatment which will improve recovery in patients suffering from SCI and reduce the severity of long-term sequalae. 2. Our studies will further our understanding of repair and recovery after spinal cord injury, and are a small step towards helping people with spinal cord injury recover more completely after these devastating injuries.

Learning Objectives: 1. To study the role of NgR1 antagonism in functional recovery after spinal cord injury 2. To study the physiological role of NgR1 using an animal model of spinal cord injury

References: Li S, Strittmatter SM (2003) Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 23:4219-4227. Chivatakarn O, Kaneko S, He Z, Tessier-Lavigne M, Giger RJ (2007) The Nogo-66 receptor NgR1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 27:7117-7124.