Effect of modulating glutamate signaling on myelinating oligodendrocytes and their development—A study in the zebrafish model,Journal of Neuroscience Research

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Effect of modulating glutamate signaling on myelinating oligodendrocytes and their development—A study in the zebrafish model
Journal of Neuroscience Research ( IF 2.9 ) Pub Date : 2021-09-14 , DOI: 10.1002/jnr.24940
Funda Turan _{1,

2} , Öznur Yilmaz ₃ , Lena Schünemann ₃ , Tobias T Lindenberg ₁ , Jeshurun C Kalanithy ₃ , Alexander Harder ₄ , Shiva Ahmadi ₅ , Türker Duman ₂ , Ryan B MacDonald ₆ , Dominic Winter ₅ , Changsheng Liu ₃ , Benjamin Odermatt _{1,

3}

Affiliation

Myelination is crucial for the development and maintenance of axonal integrity, especially fast axonal action potential conduction. There is increasing evidence that glutamate signaling and release through neuronal activity modulates the myelination process. In this study, we examine the effect of manipulating glutamate signaling on myelination of oligodendrocyte (OL) lineage cells and their development in zebrafish (zf). We use the “intensity-based glutamate-sensing fluorescent reporter” (iGluSnFR) in the zf model (both sexes) to address the hypothesis that glutamate is implicated in regulation of myelinating OLs. Our results show that glial iGluSnFR expression significantly reduces OL lineage cell number and the expression of myelin markers in larvae (zfl) and adult brains. The specific glutamate receptor agonist, L-AP4, rescues this iGluSnFR effect by significantly increasing the expression of the myelin-related genes, plp1b and mbpa, and enhances myelination in L-AP4-injected zfl compared to controls. Furthermore, we demonstrate that degrading glutamate using Glutamat-Pyruvate Transaminase (GPT) or the blockade of glutamate reuptake by L-trans-pyrrolidine-2,4-dicarboxylate (PDC) significantly decreases myelin-related genes and drastically declines myelination in brain ventricle-injected zfl. Moreover, we found that myelin-specific ClaudinK (CldnK) and 36K protein expression is significantly decreased in iGluSnFR-expressing zfl and adult brains compared to controls. Taken together, this study confirms that glutamate signaling is directly required for the preservation of myelinating OLs and for the myelination process itself. These findings further suggest that glutamate signaling may provide novel targets to therapeutically boost remyelination in several demyelinating diseases of the CNS.

中文翻译：

调节谷氨酸信号对髓鞘少突胶质细胞及其发育的影响——斑马鱼模型研究

髓鞘形成对于轴突完整性的发育和维持至关重要，尤其是快速轴突动作电位传导。越来越多的证据表明，谷氨酸信号传导和通过神经元活动释放可调节髓鞘形成过程。在这项研究中，我们研究了操纵谷氨酸信号传导对斑马鱼 (zf) 少突胶质细胞 (OL) 谱系细胞髓鞘形成及其发育的影响。我们在 zf 模型（两性）中使用“基于强度的谷氨酸感应荧光报告基因”（iGluSnFR）来解决谷氨酸参与调节髓鞘 OL 的假设。我们的研究结果表明，胶质 iGluSnFR 表达显着降低了幼虫 (zfl) 和成年大脑中 OL 谱系细胞数量和髓鞘标记物的表达。特异性谷氨酸受体激动剂 L-AP4，plp1b和mbpa，与对照组相比，在注射 L-AP4 的 zfl 中增强髓鞘形成。此外，我们证明使用谷氨酸-丙酮酸转氨酶 (GPT) 降解谷氨酸或通过 L-trans-pyrrolidine-2,4-dicarboxylate (PDC) 阻断谷氨酸再摄取显着降低髓鞘相关基因并显着降低脑室中的髓鞘形成-注入zfl。此外，我们发现与对照组相比，在表达 iGluSnFR 的 zfl 和成人大脑中，髓鞘特异性 ClaudinK (CldnK) 和 36K 蛋白表达显着降低。总之，这项研究证实，谷氨酸信号传导是保存髓鞘 OL 和髓鞘形成过程本身直接需要的。

更新日期：2021-09-14

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