NKCC1 Deficiency in Forming Hippocampal Circuits Triggers Neurodevelopmental Disorder: Role of BDNF-TrkB Signalling.
NKCC1 Deficiency in Forming Hippocampal Circuits Triggers Neurodevelopmental Disorder: Role of BDNF-TrkB Signalling.
复制标题
DOI：
10.3390/brainsci12040502
复制
发表时间：
2022-04-15
期刊：
影响因子：
3.3
通讯作者：
Minichiello, Liliana
中科院分区：
文献类型：
--
作者：
Szymanski, Jacek;Minichiello, Liliana
时间敏感的GABA从兴奋性到抑制性的转变在早期神经回路的发育中是关键的，并且依赖于阳离子-氯共转运体NKCC1和KCC2的发育调节表达。NKCC1由Scl12a2基因编码，通过与KCC2相反的氯输入来调节神经元Cl2−的动态平衡。NKCC1/KCC2的高表达比率在神经发育早期下降，导致GABA漂移。人类SLc12a2功能缺失突变最近被认为与一种影响神经发育的多系统障碍有关。然而，啮齿动物Nkcc1基因敲除模型的多系统表型给神经发育的研究带来了挑战。脑源性神经营养因子(BDNF)-NTRK2/TrkB信号调控神经发育过程中KCC2的表达，但其对NKCC1的影响仍存在争议。在这里，我们讨论了最近的证据支持BDNF-TrkB信号控制Nkcc1的表达和海马电路形成过程中GABA的移动。也就是说，未成熟小鼠海马齿状颗粒细胞(DGC)中NTRK2/TrkB的特异性缺失会影响它们在海马回路中的整合和成熟，并降低其靶区CA3主细胞中Nkcc1的表达，导致GABA过早移动，最终影响成年后海马区功能回路的建立和动物行为。因此，未成熟的DGC成为一个潜在的治疗靶点，因为GABA能传递对于特定的神经前体细胞在早期发育和成熟的大脑中产生齿状神经发生至关重要。
The time-sensitive GABA shift from excitatory to inhibitory is critical in early neural circuits development and depends upon developmentally regulated expression of cation-chloride cotransporters NKCC1 and KCC2. NKCC1, encoded by the SLC12A2 gene, regulates neuronal Cl− homeostasis by chloride import working opposite KCC2. The high NKCC1/KCC2 expression ratio decreases in early neural development contributing to GABA shift. Human SLC12A2 loss-of-function mutations were recently associated with a multisystem disorder affecting neural development. However, the multisystem phenotype of rodent Nkcc1 knockout models makes neurodevelopment challenging to study. Brain-Derived Neurotrophic Factor (BDNF)-NTRK2/TrkB signalling controls KCC2 expression during neural development, but its impact on NKCC1 is still controversial. Here, we discuss recent evidence supporting BDNF-TrkB signalling controlling Nkcc1 expression and the GABA shift during hippocampal circuit formation. Namely, specific deletion of Ntrk2/Trkb from immature mouse hippocampal dentate granule cells (DGCs) affects their integration and maturation in the hippocampal circuitry and reduces Nkcc1 expression in their target region, the CA3 principal cells, leading to premature GABA shift, ultimately influencing the establishment of functional hippocampal circuitry and animal behaviour in adulthood. Thus, immature DGCs emerge as a potential therapeutic target as GABAergic transmission is vital for specific neural progenitors generating dentate neurogenesis in early development and the mature brain.
登录
查看更多内容
影响因子：
6
作者：
Ben-Ari Y;Cherubini E
通讯作者：
Cherubini E
影响因子：
5.5
作者：
Chudotvorova, I;Ivanov, A;Medina, I
通讯作者：
Medina, I
DOI：
10.1152/ajpgi.2000.279.4.g707
发表时间：
2000-10-01
影响因子：
4.5
作者：
Grubb, BR;Lee, E;Boucher, RC
通讯作者：
Boucher, RC
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：
9.9
作者：
Benarroch, Eduardo E.
通讯作者：
Benarroch, Eduardo E.