Neutralizing a growth inhibitor in the spinal cord allows the cord to respond to experimental damage by connecting axons from the cortex to their appropriate spinal cord targets, according to a report in the current issue of the Journal of Neuroscience.
When nervous system development is complete, the adult nervous system keeps a check on further axonal growth in the spinal cord with various proteins that inhibit neurite outgrowth, among them Nogo-A (formerly known as NI-250). A monoclonal antibody raised against Nogo-A, IN-1, has been shown to induce spinal cord neurite outgrowth in a number of previous studies.
In the present work, Florence Bareyre, Martin Schwab, and Brigitte Haudenschild of the University of Zurich in Switzerland examine the long-term effects of treating rats with IN-1, especially in conjunction with a lesion of the corticospinal tract (CST), the only direct pathway from the sensory and motor areas of the cortex to the spinal cord. IN-1 was delivered to the cortical neurons that give rise to the CST via antibody-producing cells injected directly into the brain.
Even without the CST lesion, the antibody induced new neurite outgrowth in the spinal cord. This sprouting was poorly directed, however, as sensory fibers entered areas reserved for motor connections and vice versa. Gene chip analysis of the spinal cord revealed that the antibody treatment led to an upregulation of growth factors (BDNF, VEGF), growth-related proteins (actin, myosin, GAP-43), and transcription factors (STATs).
When the CST on one side of the body was lesioned, cortical treatment with IN-1 antibody produced an initial random sprouting of spinal cord neurites across the midline from the intact CST, followed by a reorganization into the appropriate sensory and motor target areas. After six weeks, the newly sprouted motor fibers were still intact and had arborized extensively, though some of the new sensory connections had been lost. This process was accompanied by greater expression of guidance molecules (semaphorins and slits) and neurotrophic factors (BDNF, IGFs, BMPs). Understanding these gene expression changes will be important if researchers hope to use antibodies to effect long-term recovery from CNS lesions.—Hakon Heimer
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- Bareyre FM, Haudenschild B, Schwab ME. Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J Neurosci. 2002 Aug 15;22(16):7097-110. PubMed.