Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina

Abstract

The bidirectional water channel aquaporin 4 (AQP4) is abundantly expressed in the neural tissue. The advantages and disadvantages of AQP4 neural tissue deficiency under pathological conditions, such as inflammation, and relationship with neural diseases, such as Alzheimer’s disease, have been previously reported. However, the physiological functions of AQP4 are not fully understood. Here, we evaluated the role of AQP4 in the mouse retina using Aqp4 knockout (KO) mice. Aqp4 was expressed in Müller glial cells surrounding the synaptic area between photoreceptors and bipolar cells. Both scotopic and photopic electroretinograms showed hyperactive visual responses in KO mice, gradually progressing with age. Moreover, the amplitude reduction after frequent stimuli and synaptic fatigue was more severe in KO mice. Glutamine synthetase, glutamate aspartate transporter, synaptophysin, and the inward potassium channel Kir2.1, but not Kir4.1, were downregulated in KO retinas. KIR2.1 colocalized with AQP4 in Müller glial cells at the synaptic area, and its expression was affected by Aqp4 levels in primary Müller glial cell cultures. Intraocular injection of potassium in wild-type mice led to visual function hyperactivity, as observed in Aqp4 KO mice. Mitochondria molecules, such as Pgc1α and CoxIV, were downregulated, while apoptotic markers were upregulated in KO retinas. AQP4 may fine-tune synaptic activity, most likely by regulating potassium metabolism, at least in part, via collaborating with KIR2.1, and possibly indirectly regulating glutamate kinetics, to inhibit neural hyperactivity and synaptic fatigue which finally affect mitochondria and cause neurodegeneration.Electronic supplementary materialThe online version of this article (10.1007/s12035-019-01661-2) contains supplementary material, which is available to authorized users.

Late-onset glaucoma in Yap conditional knockout mouse

“…GS levels in Müller cells were significantly decreased from two months onwards in Yap cKO retinas compared to control ones (Figure 6). Consistently with previous data we published 9 , this was followed in older animals by the downregulation of two other proteins involved in glutamate recycling, namely the inwardly rectifying potassium channel (Kir4.1) 7 and the water channel Aquaporin-4 (AQP4) 28,29 (Figure 6). Of note, although Kir4.1 was downregulated in Müller cell processes, its expression was increased at their endfeet within the ganglion cell layer.…”

The Area and Number of Intraretinal Cystoid Spaces Predict the Visual Outcome after Ranibizumab Monotherapy in Diabetic Macular Edema

“…This is consistent with previously reported findings that the non-perfusion area in the inner retinal layer corresponds to photoreceptor loss in branch retinal vein occlusion [35]. This could be due to the fact that the outer plexiform layer, where synapses of photoreceptor cells to the secondary neurons spread, is affected by DME in the inner retinal layer [36], which can cause subsequent photoreceptor loss [37][38][39].…”

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