CDK5/p35-Dependent Microtubule Reorganization Contributes to Homeostatic Shortening of the Axon Initial Segment
CDK5/p35-Dependent Microtubule Reorganization Contributes to Homeostatic Shortening of the Axon Initial Segment
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DOI：
10.1523/jneurosci.0917-22.2022
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发表时间：
2023-01-18
影响因子：
5.3
通讯作者：
Kuba, Hiroshi
中科院分区：
文献类型：
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作者：
Jahan, Israt;Adachi, Ryota;Kuba, Hiroshi
轴突起始段（AIS）的结构可塑性有助于活动的稳态控制并优化神经回路的功能;然而，其潜在机制尚未完全了解。在这项研究中，我们准备了一个切片培养含有核magnocellularis从鸡的两种性别，再现AIS可塑性在体内的大部分功能，关于其对AIS的特性和细胞类型特异性的影响，并揭示了微管重组通过激活CDK 5可塑性的基础。用高K+培养基处理培养物缩短了AIS并降低了钠电流和膜兴奋性，特别是在调谐到高频声音的神经元中，在细胞核中产生了AIS长度的色调差异。药理学分析表明，这种AIS缩短是由多种Ca 2+途径和随后的信号分子驱动的，这些信号分子通过ERK 1/2的激活聚集在CDK 5上。显性阴性CDK 5的过度表达抑制AIS缩短，而CDK 5的激活剂p35的过度表达促进AIS缩短。值得注意的是，p35（T138 A），p35的磷酸化失活突变体，没有缩短AIS。此外，微管稳定剂在p35过表达期间阻断AIS缩短，表明CDK 5/p35通过促进远端AIS处微管的分解来介导AIS缩短。这项研究强调了微管重组和CDK 5活性调节在结构AIS可塑性和调节神经元AIS特征中的重要性。
The structural plasticity of the axon initial segment (AIS) contributes to the homeostatic control of activity and optimizes the function of neural circuits; however, the underlying mechanisms are not fully understood. In this study, we prepared a slice culture containing nucleus magnocellularis from chickens of both sexes that reproduces most features of AIS plasticity in vivo, regarding its effects on characteristics of AIS and cell-type specificity, and revealed that microtubule reorganization via activation of CDK5 underlies plasticity. Treating the culture with a high-K+ medium shortened the AIS and reduced sodium current and membrane excitability, specifically in neurons tuned to high-frequency sound, creating a tonotopic difference in AIS length in the nucleus. Pharmacological analyses revealed that this AIS shortening was driven by multiple Ca2+ pathways and subsequent signaling molecules that converge on CDK5 via the activation of ERK1/2. AIS shortening was suppressed by overexpression of dominant-negative CDK5, whereas it was facilitated by the overexpression of p35, an activator of CDK5. Notably, p35(T138A), a phosphorylation-inactive mutant of p35, did not shorten the AIS. Moreover, microtubule stabilizers occluded AIS shortening during the p35 overexpression, indicating that CDK5/p35 mediated AIS shortening by promoting disassembly of microtubules at distal AIS. This study highlights the importance of microtubule reorganization and regulation of CDK5 activity in structural AIS plasticity and the tuning of AIS characteristics in neurons.