Chloride imbalance in Fragile X syndrome.
Chloride imbalance in Fragile X syndrome.
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DOI：
10.3389/fnins.2022.1008393
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发表时间：
2022
影响因子：
4.3
通讯作者：
Doll, Caleb Andrew
中科院分区：
文献类型：
--
作者：
Miles, Kaleb Dee;Doll, Caleb Andrew
离子平衡的发育变化与神经回路形成的关键标志有关，包括兴奋和抑制、神经发生和突触形成的变化。神经元的兴奋性在很大程度上是由细胞内外的离子浓度介导的，氯离子在早期神经发育事件中具有很高的影响力。例如，γ-氨基丁酸是成熟中枢神经系统的主要抑制性神经递质。然而，在发育早期，GABA可以使靶神经元去极化，GABA能去极化参与了关键的神经发育过程。GABA能神经递质从去极化输出到超极化输出的这种发育转变是由氯离子梯度的变化引起的，而氯离子梯度是由氯-转运体Nkcc1和Kcc2的相对表达产生的。有趣的是，在脆性X综合征(FXS)模型中，GABA的极性转换被延迟；FXS是最常见的遗传性神经发育障碍之一。RNA结合蛋白FMRP由脆性X信使核糖核蛋白-1(Fmr1)编码，在FXS中缺失，似乎调节氯转运蛋白的表达。这可能会显著影响FXS的表型，因为该综合征被假设源于神经回路发育的缺陷和兴奋/抑制(E/I)神经传递的不平衡。从这个角度出发，我们总结了典型的氯离子转运体的表达，并研究了Nkcc1和Kcc2在FXS模型中基因和蛋白表达的变化。然后我们讨论了氯离子转运体和神经传递复合体之间的相互作用，以及这些联系如何导致抑制性神经传递的失衡，从而可能改变成熟的神经回路。最后，我们强调了当前的治疗策略和在靶向FXS患者的Cl-转运体表达方面有希望的新方向。
Developmental changes in ionic balance are associated with crucial hallmarks in neural circuit formation, including changes in excitation and inhibition, neurogenesis, and synaptogenesis. Neuronal excitability is largely mediated by ionic concentrations inside and outside of the cell, and chloride (Cl–) ions are highly influential in early neurodevelopmental events. For example, γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). However, during early development GABA can depolarize target neurons, and GABAergic depolarization is implicated in crucial neurodevelopmental processes. This developmental shift of GABAergic neurotransmission from depolarizing to hyperpolarizing output is induced by changes in Cl– gradients, which are generated by the relative expression of Cl– transporters Nkcc1 and Kcc2. Interestingly, the GABA polarity shift is delayed in Fragile X syndrome (FXS) models; FXS is one of the most common heritable neurodevelopmental disorders. The RNA binding protein FMRP, encoded by the gene Fragile X Messenger Ribonucleoprotein-1 (Fmr1) and absent in FXS, appears to regulate chloride transporter expression. This could dramatically influence FXS phenotypes, as the syndrome is hypothesized to be rooted in defects in neural circuit development and imbalanced excitatory/inhibitory (E/I) neurotransmission. In this perspective, we summarize canonical Cl– transporter expression and investigate altered gene and protein expression of Nkcc1 and Kcc2 in FXS models. We then discuss interactions between Cl– transporters and neurotransmission complexes, and how these links could cause imbalances in inhibitory neurotransmission that may alter mature circuits. Finally, we highlight current therapeutic strategies and promising new directions in targeting Cl– transporter expression in FXS patients.
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影响因子：
5.5
作者：
Chudotvorova, I;Ivanov, A;Medina, I
通讯作者：
Medina, I
影响因子：
5.3
作者：
Cancedda, Laura;Fiumelli, Hubert;Poo, Mu-ming
通讯作者：
Poo, Mu-ming
影响因子：
3.9
作者：
Crutel V;Lambert E;Penelaud PF;Albarrán Severo C;Fuentes J;Rosier A;Hervás A;Marret S;Oliveira G;Parellada M;Kyaga S;Gouttefangeas S;Bertrand M;Ravel D;Falissard B
通讯作者：
Falissard B
DOI：
10.1093/cercor/bhy198
发表时间：
2018-11-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Awad PN;Amegandjin CA;Szczurkowska J;Carriço JN;Fernandes do Nascimento AS;Baho E;Chattopadhyaya B;Cancedda L;Carmant L;Di Cristo G
通讯作者：
Di Cristo G
影响因子：
17.1
作者：
Berry-Kravis, Elizabeth M.;Hessl, David;Hagerman, Randi J.
通讯作者：
Hagerman, Randi J.