γ-Aminobutyric A Receptor (GABAAR) Regulates Aquaporin 4 Expression in the Subependymal Zone

Abstract

Background: GABA A Rs regulate osmotic tension in prominin ϩ neural stem cells and ependymal cells.

Gamma-aminobutyric acid receptor agonists, aquaporin-4, and neuromyelitis optica: a potential link

“…Of note, the subependymal NSC are not only a source of new neurons but also of importance for the regeneration of the glial cell pool, the main target of AQP4-IgG-mediated cytotoxicity [35]. Even in the absence of complement-induced damage, AQP4-IgG-mediated blocking or internalization of AQP4 [38] in the SEZ could have severe pathological consequences: loss of AQP4 in ependymal cells and in neurosphere precursors derived from adult stem cells has been shown to cause functional and structural ependymal breakdown and impair neural precursor growth in vitro [8,34]. Systematic MRI and pathological studies on (sub) ependymal involvement in NMO seem highly warranted.…”

“…The finding that AQP4 is expressed by neural stem cells (NSCs) in the SEZ of the lateral ventricles, which also give rise to neuroblasts even throughout adulthood, and is involved in NSC proliferation [8,34] may be highly relevant for our understanding of the pathophysiology of NMO, including neuroregeneration in this condition, and deserves to be further investigated. NSCs have astroglial morphology ('type B astrocytes') and are located near AQP4-positive ependymal cells and, along with non-neurogenic astrocytes [35], render the ependymal and subependymal zones a likely target of AQP4-IgG.…”

“…1090-1095 of Medical Hypotheses we pointed out that drugs might intensify tissue damage by increasing the expression of AQP4 in astrocytes. In a very recent paper in the Journal of Biological Chemistry, Li et al now reported that the expression of AQP4 is regulated by the c-aminobutyric acid A receptor (GABA A R) in mouse brain cells [8]. We would like to draw attention to the potential pathophysiological and pharmacological implications of this intriguing finding.…”

“…Studies investigating such an effect should include cytotoxic assays to assess quantitatively the effect of GABA A R-induced AQP4 expression on AQP4 antibody-mediated cell damage and, given that GABA A R blockade led to a major reduction in the membrane expression of AQP4 by 50% in the cells examined by Li et al [8], to investigate the potential beneficial effect of GABA A R antagonists such as flumazenil in NMO disease models.…”

Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

“…Aquaporin-4 (AQP4) and arterial pulsation are two main driving forces in the glymphatic pathway 4, 15 . The GABA-A receptor co-localizes with AQP4 in brain tissue 16, 17 . In addition, glutamate has been shown to influence vascular smooth muscle cell function, which is associated with pulsation 18 .…”