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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,2]]},"abstract":"<jats:p>\n                    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, \u03b24-spectrin, voltage-gated sodium channels, and neurofascin. Crucially, unlike wild-type AISs, which shorten in response to stimulation by high K\n                    <jats:sup>+<\/jats:sup>\n                    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 early stage but failed to undergo the developmental shortening observed in wild-type neurons; by postnatal day 60, this resulted in elongated AISs and increased neuronal excitability in these regions. Thus, the gAnkG protein mutation impairs activity-dependent AIS plasticity, leading to abnormal neuronal excitability and behavioral deficits.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513363122","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T20:13:16Z","timestamp":1764015196000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Impaired AIS plasticity in ankyrin-G mutant mice alters cortical excitability and behavior"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9481-4322","authenticated-orcid":false,"given":"Min","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi Province, China"]},{"name":"Department of Physiology and Pathophysiology, School of 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