Genetic Loss of VGLUT1 Alters Histogenesis of Retinal Glutamatergic Cells and Reveals Dynamic Expression of VGLUT2 in Cones.

IF 2.8 3区 医学 Q3 NEUROSCIENCES
Sriparna Majumdar, Vincent Wu
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引用次数: 0

Abstract

Background/Objectives: Glutamatergic neurotransmission is essential for the normal functioning of the retina. Photoreceptor to bipolar and bipolar to ganglion cell signaling is mediated by L-glutamate, which is stored in and released from vesicular glutamate transporter 1 (VGLUT1) containing synaptic vesicles. VGLUT1 is expressed postnatally, P2 onwards, and is required for the glutamatergic retinal wave observed between P10 and P12 in the developing mouse retina. P9-P13 postnatal age is critical for retinal development as VGLUT1 expressing ribbon synapses activate in the outer and inner plexiform layers, and rod/cone mediated visual signaling commences in that period. Although it has been hypothesized that glutamatergic extrinsic signaling drives cell cycle exit and initiates cellular differentiation in the developing retina, it is not clear whether intracellular, synaptic, or extrasynaptic vesicular glutamate release contributes to this process. Recent studies have attempted to decipher VGLUT's role in retinal development. Here, we investigate the potential effect of genetic loss of VGLUT1 on early postnatal histogenesis and development of retinal neural circuitry. Methods: We employed immunohistochemistry and electrophysiology to ascertain the density of glutamatergic, cholinergic, and dopaminergic cells, spontaneous retinal activity, and light responses in VGLUT1 null retina, and contrasted them with wildtype (WT) and melanopsin null retina. Results: We have demonstrated here that VGLUT1 null retina shows signs of age dependent retinal degeneration, similar to other transgenic mice models with dysfunctional photoreceptor to bipolar cell synapses. The loss of VGLUT1 specifically alters glutamatergic cell density and morphological maturation of retinal ganglion cells. Moreover, VGLUT2 expression is lost in the majority of VGLUT2 cones in the absence of VGLUT1 coexpression, except when VGLUT2 coexpresses transiently with VGLUT3 in these cones, or when VGLUT1 null mice are dark reared. Conclusions: We present the first evidence that synaptic or extrasynaptic postnatal glutamate release from VGLUT1 containing vesicles impacts histogenesis of glutamatergic cells, pruning of retinal ganglion cell dendrites and VGLUT2 expression in cones.

VGLUT1基因缺失改变视网膜谷氨酸能细胞的组织发生,揭示VGLUT2在视锥细胞中的动态表达。
背景/目的:谷氨酸神经传递对视网膜的正常功能至关重要。光感受器到双极和双极到神经节细胞的信号传导是由l -谷氨酸介导的,l -谷氨酸储存在含有突触小泡的水疱性谷氨酸转运蛋白1 (VGLUT1)中并从其释放。VGLUT1在出生后从P2开始表达,在发育中的小鼠视网膜P10和P12之间观察到的谷氨酸能视网膜波是必需的。P9-P13出生年龄对视网膜发育至关重要,因为表达VGLUT1的带状突触在内外丛状层激活,杆/锥介导的视觉信号在这一时期开始。虽然已经假设谷氨酸能外源性信号驱动细胞周期退出并启动发育中的视网膜细胞分化,但尚不清楚细胞内、突触或突触外的囊泡谷氨酸释放是否有助于这一过程。最近的研究试图破译VGLUT在视网膜发育中的作用。在这里,我们研究了VGLUT1基因缺失对出生后早期视网膜神经回路组织发生和发育的潜在影响。方法:采用免疫组织化学和电生理方法测定VGLUT1缺失视网膜中谷氨酸能、胆碱能和多巴胺能细胞的密度、自发视网膜活性和光反应,并与野生型(WT)和黑视素缺失视网膜进行对比。结果:我们在这里证明,VGLUT1缺失的视网膜显示出年龄依赖性视网膜变性的迹象,类似于其他双极细胞突触感光功能失调的转基因小鼠模型。VGLUT1的缺失特异性地改变了谷氨酸能细胞密度和视网膜神经节细胞的形态成熟。此外,在没有VGLUT1共表达的情况下,VGLUT2在大多数VGLUT2视锥细胞中表达缺失,除非VGLUT2在这些视锥细胞中与VGLUT3短暂共表达,或者VGLUT1缺失小鼠被暗养。结论:我们首次提供证据表明,含有VGLUT1的小泡在突触或突触外释放谷氨酸会影响谷氨酸能细胞的组织发生、视网膜神经节细胞树突的修剪和视锥细胞中VGLUT2的表达。
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来源期刊
Brain Sciences
Brain Sciences Neuroscience-General Neuroscience
CiteScore
4.80
自引率
9.10%
发文量
1472
审稿时长
18.71 days
期刊介绍: Brain Sciences (ISSN 2076-3425) is a peer-reviewed scientific journal that publishes original articles, critical reviews, research notes and short communications in the areas of cognitive neuroscience, developmental neuroscience, molecular and cellular neuroscience, neural engineering, neuroimaging, neurolinguistics, neuropathy, systems neuroscience, and theoretical and computational neuroscience. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.
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