DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors
| Autor: | Shunqi Wang, Xinsheng Lai, Tian Zhou, Peng Chen, Dong Lin, Baoming Li, Bing-Xing Pan, Erkang Fei, Ziyang Liu, Huifeng Jiao, Song Lu, Suqi Zou, Jianghong Liu, Qian Zhang, Li Zhu |
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| Rok vydání: | 2021 |
| Předmět: |
Male
animal structures Dendritic spine DSCAM Autism Spectrum Disorder Autism Dendritic Spines Neurogenesis Mice Transgenic Biology Rats Sprague-Dawley Mice Glutamatergic Organ Culture Techniques Chlorocebus aethiops mental disorders medicine Animals Humans Research Articles Cells Cultured NLGN1 Gene knockdown dendritic spine Cell adhesion molecule General Neuroscience fungi Somatosensory Cortex medicine.disease Rats Mice Inbred C57BL HEK293 Cells medicine.anatomical_structure COS Cells Neuron Cell Adhesion Molecules Neuroscience Synapse maturation Cellular/Molecular |
| Zdroj: | The Journal of Neuroscience |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 inDSCAMknockdown 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 STATEMENTDSCAMis 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. |
| Databáze: | OpenAIRE |
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