期刊
FRONTIERS IN MOLECULAR NEUROSCIENCE
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2018.00212
关键词
autism spectrum disorder; autism mouse models; Shank2; Shank3; Cntn4; synapse; cell surface receptors; biotinylation assay
资金
- Deutsche Forschungsgemeinschaft (DFG) [SFB1149, TPA02]
- BIU2 at Ulm University
- Virtual Institute within the Helmholtz Gesellschaft [VH-VI-510]
- DFG [Kr1879/5-1/6-1/SFB 779 TPB8]
- Bundesministerium fur Bildung und Forschung (BMBF) [FKZ: 01GQ1421B]
- EU
- Leibniz Foundation
- European Union [289581]
- Innovative Medicines Initiative Joint Undertaking grant [115300]
Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (Shank2(-/-)), Shank3 (Shank3 alpha beta(-/-)), and Cntn4 (Cntn4(-/-)) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the alpha 1 subunit of the GABA A receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2(-/-), and Shank3 alpha beta(-/-) mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions-especially in the striatum and thalamus-when compared to wildtype controls. Interestingly, even though Cntn4(-/-) mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4(-/-) mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据