Brain Advance Access originally published online on February 11, 2008
Brain 2008 131(4):1087-1098; doi:10.1093/brain/awn014
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Greatly improved neurological outcome after spinal cord compression injury in AQP4-deficient mice
1Academic Neurosurgery Unit, St George's, University of London, London SW17 0RE, UK and 2Department of Medicine and Department of Physiology, University of California, San Francisco, CA 94143-0521 USA
Correspondence to: Marios C. Papadopoulos, MD FRCS(SN), Academic Neurosurgery Unit, Room 1.122 Jenner Wing, St George's, University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK E-mail: mpapadop{at}sgul.ac.uk
Aquaporin-4 (AQP4) is a water channel protein expressed in astrocytes throughout the CNS. In brain, AQP4 facilitates water balance and glial scar formation, which are important determinants of outcome after injury. Here, we provide evidence for AQP4-dependent spinal cord swelling following compression injury, resulting in remarkably improved outcome in AQP4-null mice. Two days after transient T6 spinal cord compression injury, wild-type mice developed more severe hindlimb weakness than AQP4-null mice, as assayed by the Basso open-field motor score, inclined plane method and footprint analysis. Basso motor scores were 1.3 ± 0.5 (wild-type) versus 4.9 ± 0.6 (AQP4-null) (SE, P < 0.001). Improved motor outcome in AQP4-null mice was independent of mouse strain and persisted at least 4 weeks. AQP4-null mice also had improved sensory outcome at 2 days, as assessed by spinal somatosensory evoked responses, with signal amplitudes 
10 µV (uninjured), 1.7 ± 0.7 µV (wild-type) and 6.4 ± 1.3 µV (AQP4-null) (P < 0.01). The improved motor and sensory indices in AQP4-null mice corresponded to remarkably less neuronal death and myelin vacuolation, as well as reduced spinal cord swelling and intraparenchymal spinal cord pressure measured at T6 at 2 days after injury. AQP4 immunoreactivity at the injury site was increased in grey and white matter at 48 h. Taken together, our findings indicate that AQP4 provides a major route for excess water entry into the injured spinal cord, which in turn causes spinal cord swelling and elevated spinal cord pressure. Our data suggest AQP4 inhibition or downregulation as novel early neuroprotective manoeuvres in spinal cord injury.
Key Words: aquaporin-4; astrocyte; oedema; spinal cord injury; water channel
Abbreviations: AQP4, aquaporin-4; AQP4+/+, wildtype; AQP4–/–, AQP4-null; BMS, Basso Mouse Scale; EBD, Evans blue dye; ECS, extracellular space; FJC, Fluoro Jade C; GFAP, glial fibrillary acidic protein; LFB, Luxol Fast Blue; NeuN, neuronal nuclear protein; SCI, spinal cord injury; SSER, spinal somatosensory evoked response
Received October 9, 2007. Revised December 21, 2007. Accepted January 18, 2008.