Majumdar Sriparna, Wu Vincent
Department of Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Computer Science Department, City College of San Francisco, San Francisco, CA 94112, USA.
Brain Sci. 2025 Sep 22;15(9):1024. doi: 10.3390/brainsci15091024.
: 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. : 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. : 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. : 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.
谷氨酸能神经传递对于视网膜的正常功能至关重要。光感受器到双极细胞以及双极细胞到神经节细胞的信号传递由L-谷氨酸介导，L-谷氨酸储存于含有囊泡谷氨酸转运体1（VGLUT1）的突触小泡中并从中释放。VGLUT1在出生后（从出生后第2天起）表达，并且是发育中小鼠视网膜在出生后第10天到第12天观察到的谷氨酸能视网膜波所必需的。出生后第9 - 13天对于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，并且视杆/视锥介导的视觉信号在这一时期开始。尽管有假说认为谷氨酸能外在信号驱动发育中的视网膜细胞退出细胞周期并启动细胞分化，但尚不清楚细胞内、突触或突触外囊泡谷氨酸释放是否参与这一过程。最近的研究试图解读VGLUT在视网膜发育中的作用。在此，我们研究VGLUT1基因缺失对出生后早期组织发生和视网膜神经回路发育的潜在影响。
我们采用免疫组织化学和电生理学方法来确定VGLUT1基因敲除视网膜中谷氨酸能、胆碱能和多巴胺能细胞的密度、视网膜自发活动以及光反应，并将它们与野生型（WT）和黑视蛋白基因敲除视网膜进行对比。
我们在此证明VGLUT1基因敲除视网膜显示出年龄依赖性视网膜变性的迹象，类似于其他光感受器到双极细胞突触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以及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，大多数VGLUT2视锥细胞中VGLUT2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基因敲除小鼠在黑暗环境中饲养。
我们提供了首个证据，表明含有VGLUT1的囊泡在出生后突触或突触外释放的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以及视锥细胞中VGLUT2的表达。
