Aquaporin4 Knockout Aggravates Early Brain Injury Following Subarachnoid Hemorrhage Through Impairment of the Glymphatic System in Rat Brain

  • E. Liu
  • Linlin Sun
  • Yixuan Zhang
  • Aibo Wang
  • Junhao YanEmail author
Part of the Acta Neurochirurgica Supplement book series (NEUROCHIRURGICA, volume 127)


Background: It is reported that the expression of aquaporin4 (AQP4) in the brain is increased and leads to the brain edema after subarachnoid hemorrhage (SAH). In this study, by using AQP4 knockout rat model, the opposite role of AQP4 in early brain injury following SAH through modulation of interstitial fluid (ISF) transportation in the brain glymphatic system had been explored.

Methods: The SAH model was established using endovascular perforation method, the AQP4 knockout rat model was generated using TALENs (transcription activator-like (TAL) effector nucleases) technique. The animals were randomly divided into four groups: sham (n = 16), AQP4−/−sham (n = 16), SAH (n = 24), and AQP4−/−SAH groups (n = 27). The roles of AQP4 in the brain water content and neurological function were detected. In addition, immunohistochemistry and Nissl staining were applied to observe the effects of AQP4 on the blood–brain barrier (BBB) integrity and the loss of neurons in the hippocampus. To explore the potential mechanism of these effects, the distribution of Gd-DTPA (interstitial fluid indicator) injected from cisterna magna was evaluated with MRI.

Results: Following SAH, AQP4 knockout could significantly increase the water content in the whole brain and aggravate the neurological deficits. Furthermore, the loss of neuron and BBB disruption in hippocampus were also exacerbated. The MRI results indicated that the ISF transportation in the glymphatic system of AQP4 deficit rat was significantly injured.

Conclusion: AQP4 facilitates the ISF transportation in the brain to eliminate the toxic factors; AQP4 knockout will aggravate the early brain injury following SAH through impairment of the glymphatic system.


Aquaporin4 Early brain injury Subarachnoid hemorrhage Glymphatic system Rat 



This work was supported by the National Natural Science Foundation of China (Grant No. 31471028) and the interdisciplinary medicine Seed Fund of Peking University (Grant No. BMU2018MC001).

Conflict of Interest: The authors declare that they have no conflict of interest.


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • E. Liu
    • 1
  • Linlin Sun
    • 1
  • Yixuan Zhang
    • 1
  • Aibo Wang
    • 2
  • Junhao Yan
    • 1
    • 2
    Email author
  1. 1.Department of Anatomy and HistologySchool of Basic Medical Sciences, Peking UniversityBeijingChina
  2. 2.Beijing Key Lab of Magnetic Resonance Imaging TechnologyBeijingChina

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