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The Journal of Neuroscience, August 6, 2003, 23(18):7034-7044
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Synergistic Effects of Brain-Derived Neurotrophic Factor and Chondroitinase ABC on Retinal Fiber Sprouting after Denervation of the Superior Colliculus in Adult Rats
Daniela Tropea, * Matteo Caleo, * andLamberto Maffei Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, and Scuola Normale Superiore, 56100 Pisa, Italy
Damage to the adult CNS often causes devastating and permanent deficits because of the limited capacity of the brain for anatomical reorganization. The finding that collateral sprouting of uninjured fiber tracts mediates recovery of function prompts the search for experimental strategies that stimulate axonal plasticity after CNS trauma. Here we characterize treatments that promote the sprouting of undamaged retinal afferents into the denervated superior colliculus (SC) after a partial retinal lesion in the adult rat. Delivery of brain-derived neurotrophic factor (BDNF) was performed to enhance the intrinsic potential of retinal ganglion cells to reelongate their axons. Reduction of the neurite growth-inhibitory properties of the adult SC was accomplished via treatment with chondroitinase ABC (C-ABC), which degrades chondroitin sulfate proteoglycans. Retinal axons were labeled via intraocular injections of fluorescently tagged cholera toxin B subunit, and fiber sprouting within the denervated SC was measured by quantitative laser-scanning confocal microscopy 1 week after the retinal lesion. We found that both the administration of BDNF and the injection of C-ABC induce significant sprouting of retinal afferents into the collicular scotoma. Remarkably, the combined treatment with BDNF and C-ABC showed synergistic effects on axon growth. Colocalization analysis with anti-synapsin antibodies demonstrated synapse formation by the sprouting axons. These results suggest that the combined treatment with BDNF and C-ABC can be relevant in therapies for the repair of the damaged adult CNS.
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Figure 1. A, Representative example of the ventrotemporal quadrant of a whole-mount lesioned retina in which retinal fibers were retrogradely labeled with DiI. The portion of the retina containing axotomized RGCs is clearly visible (bottom right). An arrow points to the optic disk. V, Ventral; T, temporal. Scale bar, 750 µm. B, Neurolucida drawing of a flat-mount lesioned retina. The extent of the retinal damage is shown in gray. V, Ventral; T, temporal. C, Confocal image of a coronal section through the colliculus of a lesioned animal that was intravitreally injected with Alexa 594-conjugated CTB. The collicular scotoma is visible as the unstained area on the medial part of the superficial gray (left). The three boxes indicate the locations of the fields used for the quantitative analysis: region 1 within the undeprived SC and regions 2 and 3 at the border and in the center of the scotoma, respectively. Scale bar, 200 µm. D, Tridimensional reconstruction of the right SC (thin lines) containing the collicular scotoma (thick lines). P, Posterior; A, anterior; M, medial; L, lateral. E, F, Retinal fiber density at 7 and 21 d after the lesion. Neither at the border (E) nor in the center of the scotoma (F) are there significant differences between the two time points. Error bars indicate SE. For each bar, n = 6 - 8 rats.
Key words: CNS injury; brain-derived neurotrophic factor; chondroitinase ABC; proteoglycans; fiber sprouting; synaptic reorganization
Received Nov. 1, 2002; revised May. 27, 2003; accepted Jun. 2, 2003.
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