Wang Han, Li Yu, Li Xin, Sun Zehui, Yu Fengdan, Pashang Abolghasem, Kulasiri Don, Li Hung Wing, Chen Huan, Hou Hongwei, Zhang Yan
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, 100871, China.
Beijing Life Science Academy, Beijing, 102200, China.
Adv Sci (Weinh). 2025 Mar;12(9):e2407405. doi: 10.1002/advs.202407405. Epub 2025 Jan 13.
The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption of ciliary function has been implicated in neuronal circuit disorders and aberrant neuronal excitability. However, the precise mechanisms remain elusive. To study the link between the primary cilia and neuronal excitability, manipulation of somatostatin receptor 3 (SSTR3) is investigated, as an example of how alterations in ciliary signaling may affect neuronal activity. It is found that aberrant SSTR3 expression perturbed not only ciliary morphology but also disrupted ciliary signaling cascades. Genetic deletion of SSTR3 resulted in perturbed spatial memory and synaptic plasticity. The axon initial segment (AIS) is a specialized region in the axon where action potentials are initiated. Interestingly, loss of ciliary SSTR3 led to decrease of Akt-dependent cyclic AMP-response element binding protein (CREB)-mediated transcription at the AIS, specifically downregulating AIS master organizer adaptor protein ankyrin G (AnkG) expression. In addition, alterations of other ciliary proteins serotonin 6 receptor (5-HT6R)and intraflagellar transport protein 88 (IFT88) also induced length changes of the AIS. The findings elucidate a specific interaction between the primary cilia and AIS, providing insight into the impact of the primary cilia on neuronal excitability and circuit integrity.
初级纤毛作为环境信号的关键介质，在神经元反应中发挥着至关重要的作用。纤毛功能的破坏与神经元回路紊乱和异常的神经元兴奋性有关。然而，确切的机制仍然不清楚。为了研究初级纤毛与神经元兴奋性之间的联系，以生长抑素受体3（SSTR3）的调控为例，探讨纤毛信号改变如何影响神经元活动。研究发现，异常的SSTR3表达不仅扰乱了纤毛形态，还破坏了纤毛信号级联反应。SSTR3的基因缺失导致空间记忆和突触可塑性受损。轴突起始段（AIS）是轴突中的一个特殊区域，动作电位在此起始。有趣的是，纤毛SSTR3的缺失导致AIS处Akt依赖的环磷酸腺苷反应元件结合蛋白（CREB）介导的转录减少，特别是下调AIS主要组织者衔接蛋白锚蛋白G（AnkG）的表达。此外，其他纤毛蛋白血清素6受体（5-HT6R）和鞭毛内运输蛋白88（IFT88）的改变也诱导了AIS的长度变化。这些发现阐明了初级纤毛与AIS之间的特定相互作用，为初级纤毛对神经元兴奋性和回路完整性的影响提供了见解。
