中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (2): 367-374.doi: 10.4103/1673-5374.286972

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

抑制γ-氨基丁酸A型受体亚型GABAA-ρ诱导斑马鱼的视网膜再生

  

  • 出版日期:2021-02-15 发布日期:2020-12-04
  • 基金资助:

    这项工作得到了NIH R01EY024354-S1和UO1 EY027265给JGP和T32 EY021453的资助,以及史蒂文森家族和Gisela Mosig捐赠给范德比尔特大学的支持

Inhibition of GABAA-ρ receptors induces retina regeneration in zebrafish

Matthew R. Kent, Nergis Kara, James G. Patton*   

  1. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
  • Online:2021-02-15 Published:2020-12-04
  • Contact: James G. Patton, PhD, James.G.Patton@Vanderbilt.edu.
  • Supported by:
    This work was supported by grants from the NIH R01EY024354-S1 and UO1 EY027265 to JGP, and T32 EY021453, as well as additional support from the Stevenson family and Gisela Mosig endowments to Vanderbilt University.

摘要:

视网膜疾病的一种潜在治疗方法是诱导内源性Müller胶质细胞产生再生反应,以替换受损的神经元。实验试图了解斑马鱼视网膜再生的机制,以便确定诱导哺乳动物视网膜再生的治疗靶标。作者曾应用药理学和遗传学方法来抑制未损坏的斑马鱼视网膜中的γ-氨基丁酸AGABAA受体,并表明这种抑制作用可以诱导视网膜再生,该作用可通过Müller胶质细胞的去分化和Müller胶质细胞来源的增殖祖细胞的出现来衡量。此次实验表明抑制GABAA受体亚型GABAA可以诱导基于Müller胶质细胞的视网膜再生反应。基因表达分析表明,抑制GABAA-ρ受体表达可引起典型的视网膜再生反应。实验结果表明斑马鱼视网膜细胞死亡或损伤后γ-氨基丁酸水平降低可诱导视网膜再生。

https://orcid.org/0000-0001-5749-0870 (James G. Patton)

关键词: γ-氨基丁酸, 吗啉代Müller神经胶质, 神经递质再生, 视网膜干细胞, 斑马鱼

Abstract: A potential treatment for retinal diseases is to induce an endogenous Müller glia (MG)-derived regenerative response to replace damaged neurons. In contrast to mammalian MG, zebrafish MG are capable of mediating spontaneous regeneration. We seek to define the mechanisms that enable retina regeneration in zebrafish in order to identify therapeutic targets to induce mammalian retina regeneration. We previously used pharmacological and genetic methods to inhibit gamma aminobutyric acid A (GABAA) receptors in undamaged zebrafish retinas and showed that such inhibition could induce initiation of retina regeneration, as measured by the dedifferentiation of MG and the appearance of 
MG-derived proliferating progenitor cells. Here, we show that inhibition of a pharmacologically distinct subset of GABAA receptors (GABAA-ρ) can also induce retina regeneration. Dual inhibition of both GABA receptor subtypes led to enhanced retina regeneration. Gene expression analyses indicate that inhibition of GABAA-ρ receptors induces a canonical retinal regenerative response. Our results support a model in which decreased levels of GABA, such as would occur after retinal cell death or damage, induce dedifferentiation of MG and the generation of proliferating progenitor cells during zebrafish retina regeneration. Animal experiments were approved by the Vanderbilt’s Institutional Animal Care and Use Committee (Protocol M1800200) on January 29, 2019.

Key words: gamma aminobutyric acid, morpholino, Müller glia, neurotransmitter, regeneration, retina, stem cells, zebrafish