• Impaired AIS plasticity in ank...

*Result*: Impaired AIS plasticity in ankyrin-G mutant mice alters cortical excitability and behavior.

Title:
Impaired AIS plasticity in ankyrin-G mutant mice alters cortical excitability and behavior.
Authors:
Li M; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Zhao B; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Lu Z; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Zhe L; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Han Y; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Chen Y; Department of Biophysics, Institute of Medical Engineering, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Wang H; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Wang Y; Department of Rehabilitation Medicine, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai 200062, China., Wu C; Department of Biophysics, Institute of Medical Engineering, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China., Zhang M; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, Guangdong province 518036, China.; School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong province 518055, China., Chen K; Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, Guangdong province 518036, China., Yang R; Institute of Neuroscience, Translational Medicine Institute, Health Science Center, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.; Department of Anesthesiology and Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China.
Source:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2025 Dec 02; Vol. 122 (48), pp. e2513363122. Date of Electronic Publication: 2025 Nov 24.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Imprint Name(s):
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:
Ankyrins*/genetics , Ankyrins*/metabolism , Neuronal Plasticity*/physiology , Neuronal Plasticity*/genetics , Axon Initial Segment*/metabolism , Axon Initial Segment*/physiology , Behavior, Animal* , Cerebral Cortex*, Neurons/metabolism ; Axons/metabolism ; Animals ; Mice ; Gene Knock-In Techniques ; Mutation ; Male ; Action Potentials
Comments:
Comment in: Proc Natl Acad Sci U S A. 2026 Jan 13;123(2):e2530592122. doi: 10.1073/pnas.2530592122.. (PMID: 41499407)
Grant Information:
32271016 MOST | National Natural Science Foundation of China (NSFC); 82101586 MOST | National Natural Science Foundation of China (NSFC); 32071370 MOST | National Natural Science Foundation of China (NSFC); S201101002 Shenzhen Bay Laboratory (SZBL)
Contributed Indexing:
Keywords: ankyrin-G; axon initial segment; intrinsically disordered protein; neurodevelopmental disorders; neuron plasticity
Substance Nomenclature:
0 (Ankyrins)
0 (Ank3 protein, mouse)
Entry Date(s):
Date Created: 20251124 Date Completed: 20251124 Latest Revision: 20260107
Update Code:
20260130
PubMed Central ID:
PMC12685073
DOI:
10.1073/pnas.2513363122
PMID:
41284870
Database:
MEDLINE

*Further Information*

*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<sup>+</sup> 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.*

*Competing interests statement:The authors declare no competing interest.*