title: Aquaporin-4 mitigates retrograde degeneration of rubrospinal neurons by facilitating edema clearance and glial scar formation after spinal cord injury in mice.
abstract: Atrophy of upper motor neurons hampers axonal regeneration and functional recovery following spinal cord injury (SCI). Apart from the severity of primary injury, a series of secondary pathological damages including spinal cord edema and glial scar formation affect the fate of injured upper motor neurons. The aquaporin-4 (AQP4) water channel plays a critical role in water homeostasis and migration of astrocytes in the central nervous system, probably offering a new therapeutic target for protecting against upper motor neuron degeneration after SCI. To test this hypothesis, we examined the effect of AQP4 deficiency on atrophy of rubrospinal neurons after unilateral rubrospinal tract transection at the fourth cervical level in mice. AQP4 gene knockout (AQP4-/-) mice exhibited high extent of spinal cord edema at 72 h after lesion compared with wild-type littermates. AQP4-/- mice showed impairments in astrocyte migration toward the transected site with a greater lesion volume at 1 week after surgery and glial scar formation with a larger cyst volume at 6 weeks. More severe atrophy and loss of axotomized rubrospinal neurons as well as axonal degeneration in the rubrospinal tract rostral to the lesion were observed in AQP4-/- mice at 6 weeks after SCI. AQP4 expression was downregulated at the lesioned spinal segment at 3 days and 1 week after injury, but upregulated at 6 weeks. These results demonstrated that AQP4 not only mitigates spinal cord damage but also ameliorates retrograde degeneration of rubrospinal neurons by promoting edema clearance and glial scar formation after laceration SCI. This finding supports the notion that AQP4 may be a promising therapeutic target for SCI.
authors.affiliation: Jiangsu Province Key Laboratory of Neurodegeneration, Department of Anatomy, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Jun-Ying
authors.initials: JY
authors.lastname: Gao
authors.forename: Xiu-Miao
authors.initials: XM
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Kong
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Xiao
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Shields
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency*; D002574:Cervical Vertebrae / Q000378:metabolism / Q000473:pathology; D002921:Cicatrix / Q000378:metabolism* / Q000473:pathology; D004487:Edema / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012012:Red Nucleus / Q000378:metabolism / Q000473:pathology; D012183:Retrograde Degeneration / Q000378:metabolism* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4