Departments of Ophthalmology & Visual Science, Yale University, New Haven, Connecticut 06511.
Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06511.
J Neurosci. 2024 Jun 19;44(25):e1379232024. doi: 10.1523/JNEUROSCI.1379-23.2024.
Vertebrate vision begins with light absorption by rod and cone photoreceptors, which transmit signals from their synaptic terminals to second-order neurons: bipolar and horizontal cells. In mouse rods, there is a single presynaptic ribbon-type active zone at which the release of glutamate occurs tonically in the dark. This tonic glutamatergic signaling requires continuous exo- and endocytosis of synaptic vesicles. At conventional synapses, endocytosis commonly requires dynamins: GTPases encoded by three genes (), which perform membrane scission. Disrupting endocytosis by dynamin deletions impairs transmission at conventional synapses, but the impact of disrupting endocytosis and the role(s) of specific dynamin isoforms at rod ribbon synapses are understood incompletely. Here, we used cell-specific knock-outs (KOs) of the neuron-specific and to investigate the functional roles of dynamin isoforms in rod photoreceptors in mice of either sex. Analysis of synaptic protein expression, synapse ultrastructure, and retinal function via electroretinograms (ERGs) showed that dynamins 1 and 3 act redundantly and are essential for supporting the structural and functional integrity of rod ribbon synapses. Single KO showed no phenotype, and single KO only modestly reduced synaptic vesicle density without affecting vesicle size and overall synapse integrity, whereas double KO impaired vesicle endocytosis profoundly, causing enlarged vesicles, reduced vesicle density, reduced ERG responses, synaptic terminal degeneration, and disassembly and degeneration of postsynaptic processes. Concurrently, cone function remained intact. These results show the fundamental redundancy of dynamins 1 and 3 in regulating the structure and function of rod ribbon synapses.
脊椎动物的视觉始于视杆和视锥光感受器对光的吸收，这些光感受器将信号从其突触末端传递到二级神经元：双极细胞和水平细胞。在小鼠视杆细胞中，在单一的突触前带状活跃区存在持续的谷氨酸释放，这种持续的谷氨酸能信号需要突触小泡的外排和内吞作用。在传统的突触中，内吞作用通常需要动力蛋白：由三个基因编码的 GTPases()，它们执行膜分裂。通过动力蛋白缺失破坏内吞作用会损害传统突触的传递，但破坏内吞作用的影响以及特定动力蛋白同工型在杆状带突触中的作用尚不完全清楚。在这里，我们使用神经元特异性和的细胞特异性敲除（KOs）来研究在雄性和雌性小鼠的视杆细胞中动力蛋白同工型的功能作用。通过视网膜电图（ERGs）分析突触蛋白表达、突触超微结构和视网膜功能表明，动力蛋白 1 和 3 具有冗余作用，对于支持杆状带突触的结构和功能完整性是必不可少的。单一的 KO 没有表型，而单一的 KO 仅适度降低了突触小泡密度，而不影响囊泡大小和整体突触完整性，而双 KO 则严重损害了囊泡内吞作用，导致囊泡增大、囊泡密度降低、ERG 反应降低、突触末端退化以及突触后过程的解体和退化。同时，锥体功能保持完整。这些结果表明，动力蛋白 1 和 3 在调节杆状带突触的结构和功能方面具有基本的冗余性。
