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

Abstract

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.

Aquaporin-4 and Parkinson’s Disease

“…Continuous theta burst stimulation can affect glymphatic clearance via GABA activation. This approach is important for the development of amyloidogenic protein-targeted treatments [183]. Thus, the studies mentioned above show the close interplay between sleep and AQP4 function and demonstrate the importance of this scientific direction.…”

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency

“…Moreover, reports indicate that the localisation of AQP4 channels at the end-feet of perivascular astrocytes depends on their interaction with syntrophin (Neely et al, 2001), a component of the dystrophin-glycoprotein complex involved in GABA A R assembly (Bragg et al, 2006). Furthermore, glymphatic clearance was impeded by bicuculline, a GABA A antagonist, and enhanced by GABA in wildtype murine models but not those which were AQP4-null (Wu et al, 2023).…”