DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.
DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.
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DSCAM 缺陷会导致脊柱过早成熟和类似自闭症的行为。
DOI：
10.1523/jneurosci.1003-21.2021
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发表时间：
2022-01-26
期刊：
影响因子：
--
通讯作者：
Fei E
中科院分区：
文献类型：
--
作者：
Chen P;Liu Z;Zhang Q;Lin D;Song L;Liu J;Jiao HF;Lai X;Zou S;Wang S;Zhou T;Li BM;Zhu L;Pan BX;Fei E
一些细胞黏附分子(CAM)的突变导致突触形成和成熟异常，是自闭症谱系障碍(ASD)的潜在机制之一。最近发现DSCAM(唐氏综合征细胞黏附分子)是自闭症的高危基因。然而，目前仍不清楚DSCAM在ASD中的作用。在这里，我们表明，DSCAM的表达在突触成熟后下调，并且DSCAM缺乏导致出生后早期树突棘成熟加速。在机制上，DSCAM的胞外区与神经连接蛋白1(NLGN1)相互作用，从而阻断NLGN1-Neurexin1β(NRXN1β)的相互作用。DSCAM胞外区能够挽救DSCAM基因敲除神经元中的脊髓过度成熟。DSCAM缺陷小鼠的早熟脊椎在发育中的皮质中显示谷氨酸能传递增加，并诱发自闭症样行为，如社会新颖性缺陷和重复行为。因此，DSCAM可能是一种抑制因子，可以防止脊柱过早成熟和谷氨酸能过度传递，其缺陷可能导致自闭症样行为。我们的研究为ASDS的潜在病理生理机制提供了新的见解。根据大规模测序分析，DSCAM不仅与唐氏综合症有关，而且是一种强烈的自闭症风险基因。然而，目前还不清楚DSCAM到底是如何导致自闭症的。在小鼠中，神经元和星形胶质细胞特异的DSCAM缺陷或锥体神经元特异的DSCAM缺陷导致自闭症样行为和空间记忆增强。此外，DSCAM在锥体神经元中的敲除或敲除导致树突棘的成熟增加。从机制上讲，DSCAM胞外区与NLGN1结合，抑制NLGN1-NRXN1的β相互作用，从而挽救DSCAM缺乏所致的脊柱异常成熟。我们的研究表明，DSCAM负向调节脊柱成熟，DSCAM缺陷导致脊柱过度成熟和自闭症样行为，从而为自闭症潜在的病理生理机制提供了新的见解。
Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs. SIGNIFICANCE STATEMENT DSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1β interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.