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乙醇和大麻素通过 Sonic Hedgehog 和 Fibroblast Growth Factor 依赖的机制调节斑马鱼 GABA 能神经元的发育和行为。

Ethanol and Cannabinoids Regulate Zebrafish GABAergic Neuron Development and Behavior in a Sonic Hedgehog and Fibroblast Growth Factor-Dependent Mechanism.

机构信息

From the, Integrated Biosciences Program, (OB-A), North Carolina Central University, Durham, North Carolina.

Julius L. Chambers Biomedical/Biotechnology Research Institute, (OB-A, C-Z, GJC), North Carolina Central University, Durham, North Carolina.

出版信息

Alcohol Clin Exp Res. 2020 Jul;44(7):1366-1377. doi: 10.1111/acer.14383. Epub 2020 Jun 18.

DOI:10.1111/acer.14383
PMID:32472575
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7572643/
Abstract

BACKGROUND

Ethanol (EtOH) has diverse effects on nervous system development, which includes development and survival of GABAergic neurons in a sonic hedgehog (Shh) and fibroblast growth factor (Fgf)-dependent mechanism. Cannabinoids also function as inhibitors of Shh signaling, raising the possibility that EtOH and cannabinoids may interact to broadly disrupt neuronal function during brain development.

METHODS

Zebrafish embryos were exposed to a range of EtOH and/or cannabinoid receptor 1 (CB1R) agonist concentrations at specific developmental stages, in the absence or presence of morpholino oligonucleotides that disrupt shh expression. In situ hybridization was employed to analyze glutamic acid decarboxylase (gad1) gene expression as a marker of GABAergic neuron differentiation, and zebrafish behavior was analyzed using the novel tank diving test as a measure of risk-taking behavior.

RESULTS

Combined acute subthreshold EtOH and CB1R agonist exposure results in a marked reduction in gad1 mRNA expression in zebrafish forebrain. Consistent with the EtOH and cannabinoid effects on Shh signaling, fgf8 mRNA overexpression rescues the EtOH- and cannabinoid-induced decrease in gad1 gene expression and also prevents the changes in behavior induced by EtOH and cannabinoids.

CONCLUSIONS

These studies provide evidence that forebrain GABAergic neuron development and zebrafish risk-taking behavior are sensitive to both EtOH and cannabinoid exposure in a Shh- and Fgf-dependent mechanism, and provide additional evidence that a signaling pathway involving Shh and Fgf crosstalk is a critical target of EtOH and cannabinoids in FASD.

摘要

背景

乙醇（EtOH）对神经系统发育有多种影响，包括在 sonic hedgehog（Shh）和 fibroblast growth factor（Fgf）依赖性机制下 GABA 能神经元的发育和存活。大麻素也作为 Shh 信号的抑制剂起作用，这增加了 EtOH 和大麻素可能相互作用以在大脑发育过程中广泛破坏神经元功能的可能性。

方法

在特定的发育阶段，将斑马鱼胚胎暴露于一系列 EtOH 和/或大麻素受体 1（CB1R）激动剂浓度下，在不存在或存在破坏 shh 表达的 morpholino 寡核苷酸的情况下。通过原位杂交分析谷氨酸脱羧酶（gad1）基因表达作为 GABA 能神经元分化的标志物，并用新的坦克潜水试验分析斑马鱼行为作为冒险行为的衡量标准。

结果

急性亚阈值 EtOH 和 CB1R 激动剂联合暴露导致斑马鱼前脑 gad1 mRNA 表达明显减少。与 EtOH 和大麻素对 Shh 信号的作用一致，fgf8 mRNA 过表达挽救了 EtOH 和大麻素诱导的 gad1 基因表达减少，并防止了 EtOH 和大麻素诱导的行为变化。

结论

这些研究提供的证据表明，大脑 GABA 能神经元发育和斑马鱼冒险行为对 Shh 和 Fgf 依赖性机制中的 EtOH 和大麻素暴露敏感，并提供了额外的证据表明涉及 Shh 和 Fgf 串扰的信号通路是 FASD 中 EtOH 和大麻素的关键靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/da89373a9385/nihms-1614551-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/02194e9b1c13/nihms-1614551-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/8797cf6a80cb/nihms-1614551-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/f98dbcc19642/nihms-1614551-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/22e8685ef21f/nihms-1614551-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/f10840306b25/nihms-1614551-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/7bb13e69d90d/nihms-1614551-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/49b0ff2406b3/nihms-1614551-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/da89373a9385/nihms-1614551-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/02194e9b1c13/nihms-1614551-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/d0dfe0bf50d5/nihms-1614551-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/b31cef894ac7/nihms-1614551-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/8797cf6a80cb/nihms-1614551-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/f98dbcc19642/nihms-1614551-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/22e8685ef21f/nihms-1614551-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/f10840306b25/nihms-1614551-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/7bb13e69d90d/nihms-1614551-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/49b0ff2406b3/nihms-1614551-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fab2/7572643/da89373a9385/nihms-1614551-f0010.jpg

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