Impaired AIS plasticity in ankyrin-G mutant mice alters cortical excitability and behavior

作者：Min Li, Bingqing Zhao, Zhimin Lu, Zhe Liu, Yue Han, Yating Chen, H Wang, Yu Tian Wang, Chunsheng Wu, Mingjie Zhang, Keyu Chen, Rui Yang · 发表于：Proceedings of the National Academy of Sciences · 年份：2025 · DOI：10.1073/pnas.2513363122 · 被引用次数：2 · 研究领域：Cellular transport and secretion、Neurogenesis and neuroplasticity mechanisms、Genetic Neurodegenerative Diseases

The developing brain undergoes neuroplasticity driven by learning, experience, and memory formation. The axon initial segment (AIS) is a specialized membrane domain within the proximal axon that initiates action potential. Studies have demonstrated that the AIS exhibits plasticity by altering its length and/or localization to adjust the excitability in response to neural stimuli. However, how AIS plasticity may affect brain function is unclear. The 480-kDa giant ankyrin-G protein (gAnkG) is the master organizer of AISs and nodes of Ranvier. Previously, we reported that a neurodevelopmental disorder-linked variant (Thr1861Met) in the neuron-specific domain of gAnkG causes the formation of diffused AISs in cultured ankyrin-G null neurons. Here, we generated a knock-in mouse harboring this mutation. The knock-in mice displayed impairments in motor coordination and social interaction. Neurons from these knock-in mice formed elongated AISs with no significant reduction in the accumulation of key AIS components-including ankyrin-G, β4-spectrin, voltage-gated sodium channels, and neurofascin. Crucially, unlike wild-type AISs, which shorten in response to stimulation by high K + or chemogenetics (designer receptors exclusively activated by designer drugs), the elongated AISs in mutant neurons failed to undergo such shortening, indicating a deficit in AIS plasticity. Neurons in the primary motor cortex and anterior cingulate cortex of knock-in mice exhibited AISs of normal length at e...