Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina
Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina
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DOI：
10.1007/s12035-019-01661-2
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发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Tsubota, Kazuo
中科院分区：
文献类型：
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作者：
Ozawa, Yoko;Toda, Eriko;Tsubota, Kazuo
双向水通道蛋白4（AQP4）在神经组织中大量表达。此前已报道了炎症等病理条件下AQP 4神经组织缺陷的优点和缺点，以及与阿尔茨海默病等神经疾病的关系。然而，AQP4的生理功能尚未完全了解。在这里，我们评估了AQP4在小鼠视网膜中的作用，使用Aqp4敲除（KO）小鼠。Aqp4在光感受器和双极细胞之间的突触区周围的Muller胶质细胞中表达。暗视和明视视网膜电图显示KO小鼠的视觉反应过度活跃，并随着年龄的增长而逐渐进展。此外，频繁刺激和突触疲劳后的振幅降低在KO小鼠中更严重。谷氨酰胺合成酶，谷氨酸天冬氨酸转运蛋白，突触素，内向钾通道Kir2.1，但不是Kir4.1，下调KO视网膜。KIR2.1与AQP4共定位于Muller胶质细胞的突触区，其表达受原代Muller胶质细胞培养物中AQP4水平的影响。在野生型小鼠中眼内注射钾导致视觉功能亢进，如在Aqp4 KO小鼠中观察到的。线粒体分子，如Pgc1 α和CoxIV，下调，而细胞凋亡标志物在KO视网膜上调。AQP4可以微调突触活动，最可能通过调节钾代谢，至少部分地通过与KIR2.1合作，并可能间接调节谷氨酸动力学，以抑制神经过度活跃和突触疲劳，最终影响线粒体并引起神经变性。
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 Muller 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 Muller glial cells at the synaptic area, and its expression was affected by Aqp4 levels in primary Muller 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 Pgc1 alpha 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.