Synaptic Structure Laboratory, Instituto de Investigación en Discapacidades Neurológicas (IDINE), Dept. Ciencias Médicas, Facultad de Medicina, Universidad Castilla-La Mancha, Campus Biosanitario, C/Almansa 14, 02008 Albacete, Spain.
Departamento de Sistemas Informáticos, Escuela Superior de Ingeniería Informática, Universidad de Castilla-La Mancha, 02071 Albacete, Spain.
Int J Mol Sci. 2020 Apr 2;21(7):2459. doi: 10.3390/ijms21072459.
Metabotropic γ-aminobutyric acid (GABA) receptors contribute to the control of network activity and information processing in hippocampal circuits by regulating neuronal excitability and synaptic transmission. The dysfunction in the dentate gyrus (DG) has been implicated in Alzheimer´s disease (AD). Given the involvement of GABA receptors in AD, to determine their subcellular localisation and possible alteration in granule cells of the DG in a mouse model of AD at 12 months of age, we used high-resolution immunoelectron microscopic analysis. Immunohistochemistry at the light microscopic level showed that the regional and cellular expression pattern of GABA was similar in an AD model mouse expressing mutated human amyloid precursor protein and presenilin1 (APP/PS1) and in age-matched wild type mice. High-resolution immunoelectron microscopy revealed a distance-dependent gradient of immunolabelling for GABA receptors, increasing from proximal to distal dendrites in both wild type and APP/PS1 mice. However, the overall density of GABA receptors at the neuronal surface of these postsynaptic compartments of granule cells was significantly reduced in APP/PS1 mice. Parallel to this reduction in surface receptors, we found a significant increase in GABA at cytoplasmic sites. GABA receptors were also detected at presynaptic sites in the molecular layer of the DG. We also found a decrease in plasma membrane GABA receptors in axon terminals contacting dendritic spines of granule cells, which was more pronounced in the outer than in the inner molecular layer. Altogether, our data showing post- and presynaptic reduction in surface GABA receptors in the DG suggest the alteration of the GABA-mediated modulation of excitability and synaptic transmission in granule cells, which may contribute to the cognitive dysfunctions in the APP/PS1 model of AD.
代谢型 γ-氨基丁酸 (GABA) 受体通过调节神经元兴奋性和突触传递来控制海马回路的网络活动和信息处理。齿状回 (DG) 的功能障碍与阿尔茨海默病 (AD) 有关。鉴于 GABA 受体在 AD 中的作用，为了确定它们在 AD 小鼠模型中 12 个月时 DG 颗粒细胞中的亚细胞定位和可能的改变，我们使用了高分辨率免疫电子显微镜分析。在 AD 模型小鼠（表达突变人淀粉样前体蛋白和早老素 1 (APP/PS1)）和年龄匹配的野生型小鼠中，通过光镜水平的免疫组织化学显示，GABA 的区域和细胞表达模式相似。高分辨率免疫电子显微镜显示，GABA 受体的免疫标记呈距离依赖性梯度，在野生型和 APP/PS1 小鼠的近端到远端树突均增加。然而，在 APP/PS1 小鼠中，这些颗粒细胞突触后隔室神经元表面 GABA 受体的总体密度显着降低。与这种表面受体减少平行，我们发现细胞质中 GABA 的含量显着增加。在 DG 的分子层中也在突触前部位检测到 GABA 受体。我们还发现与颗粒细胞树突棘接触的轴突末端中 GABA 受体的质膜减少，在外分子层比在内分子层更为明显。总之，我们的数据表明 DG 中 GABA 介导的兴奋性和突触传递的调制发生了前后突触减少，这可能导致 AD 的 APP/PS1 模型中的认知功能障碍。
