Loss of SynDIG1 Reduces Excitatory Synapse Maturation But Not Formation In Vivo.
Loss of SynDIG1 Reduces Excitatory Synapse Maturation But Not Formation In Vivo.
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DOI：
10.1523/eneuro.0130-16.2016
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发表时间：
2016-09
期刊：
影响因子：
3.4
通讯作者：
Díaz E
中科院分区：
文献类型：
--
作者：
Chenaux G;Matt L;Hill TC;Kaur I;Liu XB;Kirk LM;Speca DJ;McMahon SA;Zito K;Hell JW;Díaz E
修改兴奋性突触连接的强度是一种基本机制，在开发和学习过程中，通过神经回路进行了完善。突触分化诱导的基因1（Syndig1）已显示在体外调节突触强度方面起关键作用。在这里，我们研究了syndig1在体内的作用在小鼠中的作用，并破坏了Syndig1基因，而不是使用我们发现的替代flankp的条件突变体，我们发现该突变体保留了部分蛋白质产物。用报告基因盒式盒式突变小鼠插入基因陷阱，表明syndig1启动子在视网膜的胚胎发生过程中具有活性，在大脑中具有某些活性，并在小鼠海马，皮层，后脑，后脑和脊髓中发挥活性。海马CA1区域的超微结构分析显示，突触的平均PSD长度减少，并且具有成熟表型的突触数量减少。有趣的是，在Syndig1突变小鼠中，总突触数似乎增加了。电生理分析显示，在缺乏海马神经元中，AMPA和NMDA受体功能降低。从syndig1缺陷小鼠的海马切片中单个树突状刺激的谷氨酸刺激显示短期结构可塑性增加。值得注意的是，富含突触后生物化学分数的PSD-95或谷氨酸受体的总体水平保持不变。然而，依赖活性的突触发育在损失Syndig1时受到严重损害，支持其对兴奋性突触成熟的重要性。这些数据共同与一个模型一致，在该模型中，syndig1调节体内小鼠海马中兴奋性突触结构和功能的成熟。
Modification of the strength of excitatory synaptic connections is a fundamental mechanism by which neural circuits are refined during development and learning. Synapse Differentiation Induced Gene 1 (SynDIG1) has been shown to play a key role in regulating synaptic strength in vitro. Here, we investigated the role of SynDIG1 in vivo in mice with a disruption of the SynDIG1 gene rather than use an alternate loxP-flanked conditional mutant that we find retains a partial protein product. The gene-trap insertion with a reporter cassette mutant mice shows that the SynDIG1 promoter is active during embryogenesis in the retina with some activity in the brain, and postnatally in the mouse hippocampus, cortex, hindbrain, and spinal cord. Ultrastructural analysis of the hippocampal CA1 region shows a decrease in the average PSD length of synapses and a decrease in the number of synapses with a mature phenotype. Intriguingly, the total synapse number appears to be increased in SynDIG1 mutant mice. Electrophysiological analyses show a decrease in AMPA and NMDA receptor function in SynDIG1-deficient hippocampal neurons. Glutamate stimulation of individual dendritic spines in hippocampal slices from SynDIG1-deficient mice reveals increased short-term structural plasticity. Notably, the overall levels of PSD-95 or glutamate receptors enriched in postsynaptic biochemical fractions remain unaltered; however, activity-dependent synapse development is strongly compromised upon the loss of SynDIG1, supporting its importance for excitatory synapse maturation. Together, these data are consistent with a model in which SynDIG1 regulates the maturation of excitatory synapse structure and function in the mouse hippocampus in vivo.