Presynaptic development is controlled by the core active zone proteins CAST/ELKS
Presynaptic development is controlled by the core active zone proteins CAST/ELKS
复制标题
突触前发育由核心活性区蛋白 CAST/ELKS 控制
DOI：
10.1113/jp279736
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发表时间：
2019-10
影响因子：
5.5
通讯作者：
Young Samuel M. Jr.
中科院分区：
文献类型：
--
作者：
Radulovic Tamara;Dong Wei;Goral R. Oliver;Thomas Connon I;Veeraraghavan Priyadharishini;Montesinos Monica Suarez;Guerrero-Given Debbie;Goff Kevin;Lubbert Matthias;Kamasawa Naomi;Ohtsuka Toshihisa;Young Samuel M. Jr.
关键点CAST/ELKS是突触前生长的正调节因子，并且是Held发育中小鼠肾盏活动区扩张的抑制因子。CAST/ELKS调节突触前末梢中所有三种Ca（V）2亚型通道水平，而不仅仅是Ca（V）2.1。ELKS的半衰期是几天而不是几周。突触传递不受CAST/ELKS丢失的影响。CAST/ELKS参与通路调节突触前末梢的形态学特性在电路成熟的早期阶段。许多突触前活动区（AZ）蛋白在神经元回路发育的不同阶段具有多种调节作用。CAST/ELKS蛋白家族是进化上保守的突触前AZ分子，在哺乳动物CNS中调节突触前钙通道、突触传递和可塑性。然而，这些蛋白质如何调节突触发育和突触前功能，在其天然环境中发育的神经元回路尚不清楚。为了阐明CAST/ELKS在神经元突触发育和突触前功能中的作用，我们使用CAST敲除（KO）和ELKS条件性KO（CKO）小鼠来研究它们在电路成熟的早期阶段的丢失如何影响Held突触前末端的发育和功能。共聚焦Z-堆叠的形态学分析显示，CAST/ELKS的组合缺失导致花萼的表面积和体积减少。AZ超微结构分析显示，在没有CAST/ELKS的情况下，AZ尺寸增加。膜片钳记录显示所有突触前Ca（V）2通道亚型电流的减少与突触前Ca（V）2通道数量的损失相关。然而，这些变化并不损害突触传递和可塑性和突触囊泡释放动力学。我们的结论是，CAST/ELKS蛋白是突触前生长的正调控因子，是AZ扩张和Ca（V）2亚型电流和水平的抑制因子。我们建议，CAST/ELKS参与调节突触前形态学特性和Ca（V）2通道亚型的途径，并建议在神经元回路成熟的早期阶段，有发育补偿，以保持突触传递。
Key points CAST/ELKS are positive regulators of presynaptic growth and are suppressors of active zone expansion at the developing mouse calyx of Held. CAST/ELKS regulate all three Ca(V)2 subtype channel levels in the presynaptic terminal and not just Ca(V)2.1. The half-life of ELKS is on the timescale of days and not weeks. Synaptic transmission was not impacted by the loss of CAST/ELKS. CAST/ELKS are involved in pathways regulating morphological properties of presynaptic terminals during an early stage of circuit maturation. Many presynaptic active zone (AZ) proteins have multiple regulatory roles that vary during distinct stages of neuronal circuit development. The CAST/ELKS protein family are evolutionarily conserved presynaptic AZ molecules that regulate presynaptic calcium channels, synaptic transmission and plasticity in the mammalian CNS. However, how these proteins regulate synapse development and presynaptic function in a developing neuronal circuit in its native environment is unclear. To unravel the roles of CAST/ELKS in glutamatergic synapse development and in presynaptic function, we used CAST knockout (KO) and ELKS conditional KO (CKO) mice to examine how their loss during the early stages of circuit maturation impacted the calyx of Held presynaptic terminal development and function. Morphological analysis from confocal z-stacks revealed that combined deletion of CAST/ELKS resulted in a reduction in the surface area and volume of the calyx. Analysis of AZ ultrastructure showed that AZ size was increased in the absence of CAST/ELKS. Patch clamp recordings demonstrated a reduction of all presynaptic Ca(V)2 channel subtype currents that correlated with a loss in presynaptic Ca(V)2 channel numbers. However, these changes did not impair synaptic transmission and plasticity and synaptic vesicle release kinetics. We conclude that CAST/ELKS proteins are positive regulators of presynaptic growth and are suppressors of AZ expansion and Ca(V)2 subtype currents and levels during calyx of Held development. We propose that CAST/ELKS are involved in pathways regulating presynaptic morphological properties and Ca(V)2 channel subtypes and suggest there is developmental compensation to preserve synaptic transmission during early stages of neuronal circuit maturation.
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DOI：
10.1523/jneurosci.1848-05.2005
发表时间：
2005-09-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
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作者：
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影响因子：
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期刊：
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DOI：
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发表时间：
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期刊：
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影响因子：
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Xiaolu Wang;Bin Hu;Agata Zięba;Nicole G. Neumann;M. Kasper-Sonnenberg;Annegret Honsbein;G. Hultqvist;Tim Conze;W. Witt;C. Limbach;M. Geitmann;H. Danielson;Richard Kolarow;G. Niemann;V. Lessmann;M. Kilimann