自闭症谱系障碍相关分子 Lingo2 的可溶形式在神经元中发挥兴奋性突触组织者的功能。

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-23 DOI:10.1038/s41398-024-03167-5
Fumiaki Yoshida, Ryota Nagatomo, Shun Utsunomiya, Misaki Kimura, Shiyori Shun, Rena Kono, Yuma Kato, Yosuke Nao, Kazuma Maeda, Ryuta Koyama, Yuji Ikegaya, Stefan F Lichtenthaler, Sho Takatori, Hiroshi Takemoto, Koichi Ogawa, Genta Ito, Taisuke Tomita
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引用次数: 0

摘要

自闭症谱系障碍(ASD)是一种以社会交流障碍和重复行为为特征的发育障碍。近年来,母体服用丙戊酸(VPA)的自闭症药理学小鼠模型得到广泛应用。该模型中的新生幼鼠表现出神经元中兴奋和抑制(E/I)信号的异常平衡,并表现出类似 ASD 的行为。然而,这种模型的分子基础及其对人类 ASD 发病机制的影响仍然未知。通过定量分泌组分析,我们发现富亮氨酸重复和含免疫球蛋白结构域蛋白2(Lingo2)的水平在VPA模型神经元的条件培养基中上调。这种上调与兴奋性突触组织者的活动有关。研究发现,sLingo2 可诱导小鼠和人类神经元兴奋性突触的形成,用 sLingo2 处理可增加人类神经元微型兴奋性突触后电流的频率。这些发现表明,sLingo2 是一种参与 ASD 的兴奋性突触组织者,进一步了解 sLingo2 诱导兴奋性突触形成的机制有望促进我们对 ASD 发病机制的了解。
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Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons.

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social communication and repetitive behaviors. In recent years, a pharmacological mouse model of ASD involving maternal administration of valproic acid (VPA) has become widely used. Newborn pups in this model show an abnormal balance between excitatory and inhibitory (E/I) signaling in neurons and exhibit ASD-like behavior. However, the molecular basis of this model and its implications for the pathogenesis of ASD in humans remain unknown. Using quantitative secretome analysis, we found that the level of leucine-rich repeat and immunoglobulin domain-containing protein 2 (Lingo2) was upregulated in the conditioned medium of VPA model neurons. This upregulation was associated with excitatory synaptic organizer activity. The secreted form of the extracellular domain of Lingo2 (sLingo2) is produced by the transmembrane metalloprotease ADAM10 through proteolytic processing. sLingo2 was found to induce the formation of excitatory synapses in both mouse and human neurons, and treatment with sLingo2 resulted in an increased frequency of miniature excitatory postsynaptic currents in human neurons. These findings suggest that sLingo2 is an excitatory synapse organizer involved in ASD, and further understanding of the mechanisms by which sLingo2 induces excitatory synaptogenesis is expected to advance our understanding of the pathogenesis of ASD.

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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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