Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada.
Acta Neuropathol Commun. 2023 Feb 14;11(1):27. doi: 10.1186/s40478-023-01524-x.
Most research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.
大多数关于谷氨酸外溢的研究都集中在后突触谷氨酸受体过度激活的有害后果上。然而，二十年前就有人指出，海马突触的神经胶质覆盖是不对称的：星形胶质细胞对突触后部位的覆盖超过了对突触前部位的覆盖，比例为四比一。这种神经胶质不对称性的基本相关性仍未得到很好的理解。在这里，我们使用谷氨酸生物传感器 iGluSnFR，并将其表达限制在 CA3 或 CA1 神经元上，分别在突触前和突触后微环境中可视化谷氨酸动力学。我们证明，与突触后膜相比，主要星形胶质细胞谷氨酸转运蛋白-1 (GLT-1) 的抑制在突触前膜更能减缓谷氨酸的清除。AD 小鼠模型中 GLT-1 的表达早期减少，导致突触前膜而不是突触后膜的谷氨酸清除率变慢，这与突触前短期可塑性相反。总的来说，我们的数据表明，突触前特别容易受到 GLT-1 功能障碍的影响，这可能对各种脑疾病中的突触前损伤有影响。
