Castilho Áurea, Ambrósio António F, Hartveit Espen, Veruki Margaret L
Department of Biomedicine, University of Bergen, Bergen N-5009, Norway, Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3000-548, and.
Centre of Ophthalmology and Vision Sciences, Institute of Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3000-548, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal 3000-548.
J Neurosci. 2015 Apr 1;35(13):5422-33. doi: 10.1523/JNEUROSCI.5285-14.2015.
Diabetes leads to dysfunction of the neural retina before and independent of classical microvascular diabetic retinopathy, but previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages. Here, using patch-clamp recording and two-photon Ca(2+) imaging in rat retinal slices, we investigated diabetes-evoked changes in a microcircuit consisting of rod bipolar cells and their dyad postsynaptic targets, AII and A17 amacrine cells, which play an essential role in processing scotopic visual signals. AII amacrines forward their signals to ON- and OFF-cone bipolar cells and A17 amacrines provide GABAergic feedback inhibition to rod bipolar cells. Whereas Ca(2+)-permeable AMPA receptors mediate input from rod bipolar cells to both AII and A17 amacrines, diabetes changes the synaptic receptors on A17, but not AII amacrine cells. This was expressed as a change in pharmacological properties and single-channel conductance of the synaptic receptors, consistent with an upregulation of the AMPA receptor GluA2 subunit and reduced Ca(2+) permeability. In addition, two-photon imaging revealed reduced agonist-evoked influx of Ca(2+) in dendritic varicosities of A17 amacrine cells from diabetic compared with normal animals. Because Ca(2+)-permeable receptors in A17 amacrine cells mediate synaptic release of GABA, the reduced Ca(2+) permeability of these receptors in diabetic animals leads to reduced release of GABA, followed by disinhibition and increased release of glutamate from rod bipolar cells. This perturbation of neuron and microcircuit dynamics can explain the decreased dynamic range and sensitivity of scotopic vision that has been observed in diabetes.
糖尿病在经典微血管性糖尿病视网膜病变之前且与之无关的情况下，就会导致神经视网膜功能障碍，但以往的研究未能证明在最早阶段哪些神经元和神经回路会受到影响。在此，我们利用大鼠视网膜切片的膜片钳记录和双光子Ca(2+)成像技术，研究了由视杆双极细胞及其双联突触后靶点AII和A17无长突细胞组成的微回路中糖尿病诱发的变化，这些细胞在暗视觉信号处理中起重要作用。AII无长突细胞将其信号转发给ON型和OFF型视锥双极细胞，A17无长突细胞对视杆双极细胞提供GABA能反馈抑制。虽然Ca(2+)通透型AMPA受体介导视杆双极细胞向AII和A17无长突细胞的输入，但糖尿病会改变A17而非AII无长突细胞上的突触受体。这表现为突触受体药理学特性和单通道电导的变化，与AMPA受体GluA2亚基上调和Ca(2+)通透性降低一致。此外，双光子成像显示，与正常动物相比，糖尿病动物A17无长突细胞树突膨大处激动剂诱发的Ca(2+)内流减少。由于A17无长突细胞中的Ca(2+)通透型受体介导GABA的突触释放，糖尿病动物中这些受体Ca(2+)通透性降低导致GABA释放减少，随后解除抑制，视杆双极细胞谷氨酸释放增加。神经元和微回路动力学的这种扰动可以解释糖尿病中观察到的暗视觉动态范围和敏感性降低的现象。
