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Aging and disease    2018, Vol. 9 Issue (5) : 808-816     DOI: 10.14336/AD.2017.1115
Orginal Article |
The Effect of Aquaporin-4 Knockout on Interstitial Fluid Flow and the Structure of the Extracellular Space in the Deep Brain
Ze Teng1,2,  Aibo Wang1,2, Peng Wang3,  Rui Wang2, Wei Wang2,  Hongbin Han1,2,*
1Department of Radiology, Peking University Third Hospital, Beijing 100191, China
2Beijing Key Lab. of Magnetic Resonance Imaging Technology, Beijing 100191, China
3Department of Orthopedics, Peking University Third Hospital, Beijing 100191, China
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It has been reported that aquaporin-4 (AQP4) deficiency impairs transportation between the cerebrospinal fluid and interstitial fluid (ISF) as well as the clearance of interstitial solutes in the superficial brain. However, the effect of AQP4 on ISF flow in the deep brain remains unclear. This study compared the brain ISF flow in the caudate nucleus and thalamus of normal rats (NO) and AQP4 knockout rats (KO) using tracer-based magnetic resonance imaging. The rate of brain ISF flow slowed to different degrees in the two regions of KO rats’ brains. Compared with NO rats, the half-life of ISF in the thalamus of KO rats was significantly prolonged, with a corresponding decrease in the clearance coefficient. The tortuosity of the brain extracellular space (ECS) was unchanged in the thalamus of KO rats. In the caudate nucleus of KO rats, the volume fraction of the ECS and the diffusion coefficient were increased, with significantly decreased tortuosity; no significant changes in brain ISF flow were demonstrated. Combined with a change in the expression of glial fibrillary acidic protein and AQP4 in two brain regions, we found that the effect of AQP4 knockout on ISF flow and ECS structure in these two regions differed. This difference may be related to the distribution of astrocytes and the extent of AQP4 decline. This study provides evidence for the involvement of AQP4 in ISF transportation in the deep brain and provides a basis for the establishment of a pharmacokinetic model of the brain’s interstitial pathway.

Keywords Aquaporin-4      interstitial fluid      extracellular space      tracer-based magnetic resonance imaging     
Corresponding Authors: Han Hongbin   
About author: These authors contributed equally to this work.
Issue Date: 29 September 2017
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Teng Ze
Wang Aibo
Wang Peng
Wang Rui
Wang Wei
Han Hongbin
Cite this article:   
Teng Ze,Wang Aibo,Wang Peng, et al. The Effect of Aquaporin-4 Knockout on Interstitial Fluid Flow and the Structure of the Extracellular Space in the Deep Brain[J]. Aging and disease, 2018, 9(5): 808-816.
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Figure 1.  Peak map of AQP4 gene sequencing of normal (NO) and AQP4 knockout (KO) rats

Compared with NO rats, AQP4 KO rats showed a multimodal peak near the AQP4-T1 position (black arrow), indicating AQP4 gene deletion.

Figure 2.  Flow of interstitial fluid and the structure of the extracellular space in the caudate nucleus and thalamus of normal (NO) and AQP4 knockout (KO) rats

(A) Interstitial fluid flow was visualized by tracer-based magnetic resonance imaging and is shown in sagittal, axial, and coronal views. The interstitial fluid in the caudate nucleus flowed to the prefrontal and parietal cortex and finally poured into the cerebrospinal fluid. Interstitial fluid in the thalamus was restricted within its anatomical region. (B-F) In the caudate nucleus, diffusion parameters and the volume fraction of the ECS were increased in the KO group and tortuosity was decreased, but no differences were found in the local clearance rates and half-life. In the thalamus, the local clearance rates in the KO group were less than those of the NO group, the half-life in the KO group was prolonged. No difference was found in the diffusion parameters, volume fraction, and tortuosity of ECS. The data are expressed as the mean±standard deviation (SD). n=6 rats per group, **P<0.05.

Figure 3.  Protein expression of GFAP and AQP4 in the caudate nucleus and thalamus

(A, C) The expression of glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) in the thalamus was significantly higher than that in the caudate nucleus in the normal (NO) group. (B, D) AQP4 was weakly expressed in the caudate nucleus and thalamus in the AQP4 knockout (KO) group, whereas GFAP expression did not change significantly in either region. The data are expressed as the mean ± standard deviation (SD). n=6 rats per group, **P<0.05.

Figure 4.  Changes of in ISF flow in the ECS between the caudate nucleus and cortex

In normal deep brain, ISF flows from the caudate nucleus to the cortex along myelinated fibers, whereas it is cleared from the brain along paravenous routes in the cortex. The flow of ISF is facilitated by AQP4-dependent astroglial water flux, which drives fluid dispersion into the subarachnoid CSF. In the brains of knockout rats, AQP4 deficiency led to obstruction of ISF clearance and accumulation of ISF in the cortex and caudate nucleus, resulting in a decrease in tortuosity and an increase in the volume fraction and molecular diffusion rate in the ECS within the caudate nucleus.

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