GABA promotes interstitial fluid clearance in an AQP4‐dependent manner by activating the GABAAR

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin‐4 (AQP4) expressed on the perivasc...

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Bibliographic Details
Published in:Journal of neurochemistry 2023-08, Vol.166 (3), p.560-571
Main Authors: Wu, Cheng, Zhang, Qun, Feng, Yi‐Wei, Zhang, Ni, Liu, Qi, Ou, Zi‐Tong, Lin, Tuo, Ding, Qian, Li, Ge, Pei, Zhong, Lan, Yue, Xu, Guang‐Qing
Format: Article
Language:English
Subjects:
Achievement tests
Aquaporin 4
Arousal
Cerebrospinal fluid
continuous theta burst stimulation
glymphatic system
interstitial fluid
Magnetic fields
Metabolic wastes
Noradrenaline
Norepinephrine
Parenchyma
Proteins
Solutes
Transcranial magnetic stimulation
γ-Aminobutyric acid A receptors
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Summary:The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin‐4 (AQP4) expressed on the perivascular astrocytic end‐feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ‐aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAAR) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation‐continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4‐dependent manner by activating the GABAAR. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition‐related diseases. The activation of the GABAAR by GABA facilitates interstitial penetration and promotes glymphatic drainage. This process is dependent on AQP4 and may be achieved by upregulating the expression and polarity distribution of AQP4, which enhances the permeability efficiency of AQP4. Our findings reveal that non‐invasive cTBS can mimic the effects induced by GABA on glymphatic drainage, which is of particular interest. Moreover, our results provide crucial insights into the role of glymphatic dysfunction in various diseases. AQP4, aquaporin‐4; cTBS, continuous theta burst stimulation; GABA, γ‐aminobutyric acid; GABAAR, GABAA receptor.
ISSN:0022-3042
1471-4159
DOI:10.1111/jnc.15869