Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish.
Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish.
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DOI：
10.1186/s13229-022-00516-3
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发表时间：
2022-09-22
期刊：
影响因子：
6.2
通讯作者：
中科院分区：
文献类型：
--
作者：
自闭症谱系障碍（ASD）与许多神经发育障碍一样，具有复杂多样的病因。基因组测序的进展已经确定了与ASD相关的多个候选基因，包括由GRIN2B编码的NMDAR亚基GluN2B中的数十个错义和无义突变。NMDARs是谷氨酸门控离子通道，在兴奋性神经传递中具有关键的突触功能。这些蛋白质的改变如何影响神经发育尚不清楚，部分原因是在啮齿动物中敲除GluN2B是致命的。在这里，我们使用CRISPR-Cas9生成缺乏GluN2B （grin2B−/−）的斑马鱼。利用这些鱼，我们进行了一系列行为测试，并进行了全脑幼虫成像，以分析GluN2B的发育作用和功能。我们证明斑马鱼GluN2B具有与人类GluN2B相似的结构和功能特性。缺乏GluN2B （grin2B−/−）的斑马鱼出人意料地存活到成年。鉴于社会缺陷在ASD中的普遍存在，我们分析了grin2B - / -鱼的社会偏好。野生型鱼在受精后3周形成强烈的社会偏好。相比之下，这个年龄的grin2B - / -鱼表现出明显降低的社会偏好。值得注意的是，缺乏GluN2B并不会导致神经发育的广泛中断，因为grun2b−/−幼虫不会表现出自发或光诱发运动的改变，能够捕获猎物，并表现出学习能力。grin2B - / -幼虫的全脑成像显示，与人类ASD相关的皮层下抑制神经元标记物减少，但显示grin2B - / -的整体脑大小和E/I平衡与野生型相当。缺乏GluN2B的斑马鱼，虽然有助于研究GluN2B的发育作用，但不太可能模拟人类错义突变的细微功能改变，这些突变不是完全丧失功能。此外，在全脑成像时代，斑马鱼幼虫脑细分的详细哺乳动物同源性尚未完全解决。我们证明，与啮齿动物模型不同，完全缺乏NMDAR GluN2B亚基的斑马鱼可以存活到成年。值得注意的是，他们在社会行为上表现出高度的特定缺陷。因此，该斑马鱼模型为研究GluN2B在ASD病因学中的作用提供了独特的机会，并为未来的研究建立了疾病相关的体内模型。在线版本包含补充材料，可在10.1186/s13229-022-00516-3获得。
Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B−/−). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B−/−) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B−/− fish. Wild-type fish develop a strong social preference by 3 weeks post fertilization. In contrast, grin2B−/− fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B−/− larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B−/− larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B−/− is comparable to wild type. Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies. The online version contains supplementary material available at 10.1186/s13229-022-00516-3.
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影响因子：
2.9
作者：
Chen J;Lei L;Tian L;Hou F;Roper C;Ge X;Zhao Y;Chen Y;Dong Q;Tanguay RL;Huang C
通讯作者：
Huang C
影响因子：
2.5
作者：
Cox, JA;Kucenas, S;Voigt, MM
通讯作者：
Voigt, MM
DOI：
10.15585/mmwr.ss6706a1
发表时间：
2018-04-27
期刊：
Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002)
影响因子：
--
作者：
Baio J;Wiggins L;Christensen DL;Maenner MJ;Daniels J;Warren Z;Kurzius-Spencer M;Zahorodny W;Robinson Rosenberg C;White T;Durkin MS;Imm P;Nikolaou L;Yeargin-Allsopp M;Lee LC;Harrington R;Lopez M;Fitzgerald RT;Hewitt A;Pettygrove S;Constantino JN;Vehorn A;Shenouda J;Hall-Lande J;Van Naarden Braun K;Dowling NF
通讯作者：
Dowling NF
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
3
作者：
Cercato MC;Vázquez CA;Kornisiuk E;Aguirre AI;Colettis N;Snitcofsky M;Jerusalinsky DA;Baez MV
通讯作者：
Baez MV