Hypomyelination in autism-associated neuroligin-3 mutant mice impairs parvalbumin interneuron excitability, gamma oscillations, and sensory discrimination

Yongxiang He, Jiong Li, Wei Zheng, Junhong Liu, Zhaojun Dong, Lu Yang, Shuting Tang, Yanping Zou, Tianyu Gao, Yuqian Yang, Zhenpeng Mo, Shuming Wang, Yuehua He, Changyong Tang, Jianhong Luo, Jingwei Zhao, Guoqing Guo, Huiliang Li and Lin Xiao ()
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Yongxiang He: South China Normal University
Jiong Li: South China Normal University
Wei Zheng: South China Normal University
Junhong Liu: South China Normal University
Zhaojun Dong: Zhejiang University School of Medicine
Lu Yang: The Third Affiliated Hospital of Sun Yat-Sen University
Shuting Tang: South China Normal University
Yanping Zou: South China Normal University
Tianyu Gao: South China Normal University
Yuqian Yang: South China Normal University
Zhenpeng Mo: South China Normal University
Shuming Wang: South China Normal University
Yuehua He: South China Normal University
Changyong Tang: The Third Affiliated Hospital of Sun Yat-Sen University
Jianhong Luo: Zhejiang University School of Medicine
Jingwei Zhao: Zhejiang University School of Medicine
Guoqing Guo: Medical College of Jinan University
Huiliang Li: University College London
Lin Xiao: South China Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Whether and how myelin plasticity, an emerging new form of brain plasticity, is involved in autism spectrum disorder (ASD) remains unknown. Here, we identify deficits in oligodendrocyte (OL) generation and myelination in the barrel cortex (BC) of the male NL3-R451C-KI mouse model of ASD. These mice also show impaired texture recognition, disrupted gamma neuronal oscillations, and reduced excitability and myelination level in the BC-PV interneuron. These abnormalities can be rescued by a promyelinating strategy and are recapitulated by genetic blockade of myelination in Myrf-cKO mice. Furthermore, OL progenitor-specific conditional NL3 knockout mice show similar deficits in BC-PV interneuron myelination and excitability, as well as neuronal oscillation and texture recognition, closely resembling the NL3-R451C-KI phenotype. Collectively, these results demonstrate that NL3 mutations commonly cause hypomyelination and reduced excitability in BC-PV interneurons, disrupting neuronal oscillation and contributing to ASD-like sensory dysfunction. Our finding reveals a mechanism underlying ASD and highlights OLs/myelin as potential therapeutic targets for ASD.

Date: 2025
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DOI: 10.1038/s41467-025-61455-0

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