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

• Published in: Nature communications Vol. 16; no. 1; pp. 6382 - 23
• Main Authors: He, Yongxiang, Li, Jiong, Zheng, Wei, Liu, Junhong, Dong, Zhaojun, Yang, Lu, Tang, Shuting, Zou, Yanping, Gao, Tianyu, Yang, Yuqian, Mo, Zhenpeng, Wang, Shuming, He, Yuehua, Tang, Changyong, Luo, Jianhong, Zhao, Jingwei, Guo, Guoqing, Li, Huiliang, Xiao, Lin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/19; 14/28; 631/378; 631/378/2606; 64/60; 9/30; 9/74; Abnormalities; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - physiopathology; Autistic Disorder - genetics; Brain; Cell Adhesion Molecules, Neuronal - genetics; Cell Adhesion Molecules, Neuronal - metabolism; Cells; Cortex (barrel); Disease Models, Animal; Excitability; Gamma Rhythm - physiology; Humanities and Social Sciences; Information processing; Interneurons; Interneurons - metabolism; Interneurons - physiology; Localization; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; multidisciplinary; Mutation; Myelin; Myelin Sheath - metabolism; Myelin Sheath - pathology; Myelination; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural stem cells; Neuroplasticity; Oligodendroglia - metabolism; Oscillations; Parvalbumin; Parvalbumins - metabolism; Phenotypes; Plastic properties; Plasticity; Proteins; Science; Science (multidisciplinary); Sensory discrimination; Sensory integration; Somatosensory cortex; Somatosensory Cortex - metabolism; Texture recognition; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-61455-0

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. The contribution of myelin plasticity to autism spectrum disorder remains poorly understood. Here authors demonstrate that mutations in Nlgn3 lead to hypomyelination and reduced parvalbumin interneuron activity, while enhancing myelination ameliorates autism-like sensory processing deficits.