Servicio de Neurobiología-Investigación, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain; Departamento de Farmacología y Terapeútica, ITH, Facultad de Medicina, Universidad Autónoma de Madrid, IRYCIS, Avda. Arzobispo Morcillo 4, 28029, Madrid, Spain.
Unidad de Neurología Experimental, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, 28034, Spain.
Neuropharmacology. 2021 Jun 1;190:108557. doi: 10.1016/j.neuropharm.2021.108557. Epub 2021 Apr 20.
The intracellular accumulation of some amino acids (AAs), mainly glutamine, can contribute to brain edema observed during liver failure. We recently demonstrated that individual applications of high concentrations (10 mM) of some non-excitatory AAs increase the electrical resistance of hippocampal slices, indicating cell swelling. Therefore, we pondered whether an AA mixture's application might cause cell swelling at a physiological concentration range. In rat hippocampal slices, we carried out extra- and intracellular electrophysiological recordings and AAs analysis to address this question. We applied a mixture of 19 AAs at their plasmatic concentrations (Plasma solution: Ala, Gly, Gln, His, Ser, Tau, Thr, Arg, Leu, Met, Pro, Val, Asn, Cys, Phe, Ile, Lys, Tyr, and Trp). This solution was afterward divided into two according to the individual AAs at 10 mM concentration inducing synaptic potentiation (Plasma1, containing the first seven AAs of Plasma) or not (Plasma2, with the remaining AAs). Plasma application increased evoked field potentials requiring extracellular chloride. This effect was mimicked by the Plasma1 but not the Plasma2 solution. Plasma1-induced potentiation was independent of changes in release probability, basic electrophysiological membrane properties, and NMDAR activation. AAs in Plasma1 act cooperatively to accumulate intracellularly and to induce synaptic potentiation. In the presence of Plasma1, the reversible synaptic depression caused by a 40-min hypoxia period turned into an irreversible disappearance of synaptic potentials through an NMDAR-dependent mechanism. The presence of a system A transport inhibitor did not block Plasma1-mediated effects. These results indicate that cell swelling, induced by the accumulation of non-excitotoxic AAs through unidentified transporters, might foster deleterious effects produced by hypoxia-ischemia episodes.
一些氨基酸（AAs），主要是谷氨酰胺，在肝衰竭时会导致脑水种，细胞内积累。我们最近证明，高浓度（10mM）的某些非兴奋性氨基酸的单独应用会增加海马切片的电阻，表明细胞肿胀。因此，我们想知道 AA 混合物在生理浓度范围内应用是否会导致细胞肿胀。在大鼠海马切片中，我们进行了细胞外和细胞内电生理记录和 AA 分析来解决这个问题。我们应用了含有 19 种 AA 的混合物，其浓度与血浆中的 AA 浓度一致（血浆溶液：Ala、Gly、Gln、His、Ser、Tau、Thr、Arg、Leu、Met、Pro、Val、Asn、Cys、Phe、Ile、Lys、Tyr 和 Trp）。该溶液根据在 10mM 浓度下诱导突触增强的单个 AA 分为两部分（Plasma1，包含 Plasma 中的前七个 AA）或不包含（Plasma2，包含其余 AA）。Plasma 应用增加了需要细胞外氯离子的诱发场电位。这种效应由 Plasma1 模拟，但不是由 Plasma2 溶液模拟。Plasma1 诱导的增强与释放概率、基本电生理膜特性和 NMDA 受体激活无关。Plasma1 中的 AA 协同作用以在细胞内积累并诱导突触增强。在 Plasma1 存在的情况下，40 分钟缺氧期引起的可逆突触抑制转变为通过 NMDA 受体依赖性机制不可逆地消失突触电位。存在系统 A 转运抑制剂不会阻止 Plasma1 介导的作用。这些结果表明，通过未鉴定的转运蛋白积累非兴奋性氨基酸引起的细胞肿胀可能会促进缺氧缺血发作产生的有害影响。
