The Effects Of Aquaporin4Gene Knockout On Retrograde Degeneration Of Axotomized Rubrospinal Tract In Mice

Previous studies revealed that astrocyte activation, glial scar formation and decreased spinal cord edema facilitate reduced retrograde degeneration of nerve fibers after spinal cord injury (SCI). Aquaporin4(AQP4), a water transport channel highly expressed in astrocyte processes, plays a critical role in astrocyte migration and glial scar formation as well as in the water homeostasis within the central nervous system. Therefore, we speculate that AQP4may participate in the pathological course of nerve fiber degeneration after SCI. To prove this hypothesis, we performed the right rubrospinal tract transaction at the cervical4segment, and compared the motor function of the forepaws, inflammation of injured spinal segments, formation of glial scar, and degeneration of rubrospinal tract and cell bodies of rubrospinal neurons between adult AQP4gene knockout (AQP4-/-) mice and the wild-type (AQP4+/+) mice from1-6weeks after surgery. The spontaneous vertical exploration testing demonstrated that AQP4-/-mice and AQP4+/+mice lost the ability of using the right forepaw alone to explore the cylinder up to6weeks after surgery. Pathological analysis on spinal sections revealed that, compared with AQP4+/+mice, AQP4-/-mice showed increases in lesion area, deficits in migration ability of glial fibrillary acidic protein positive astrocytes toward the injured site and impaired glial scar formation. AQP4-/-mice also showed decreases in neuron-specific class III beta-tubulin positive axons in the dorsolateral tract where the rubrospinal tract are located. Furthermore, results of Nissl staining on midbrain sections and fluorogold retrograde tracing showed that axotomized rubrospinal neurons in AQP4-/-mice exhibited severe neuronal atrophy and loss, compared with those in AQP4+/+mice. In conclusion, these results demonstrated that AQP4gene knockout leads to increases in spinal lesion area, deficits in astrocyte migration and glial scar formation, subsequently exacerbates retrograde degeneration of atomized mouse rubrospinal tract.