Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome.
Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome.
复制标题
脆性 X 综合征小鼠模型中突触组成和星形胶质细胞参与的多方面变化。
DOI：
10.1038/s41598-019-50240-x
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发表时间：
2019
影响因子：
4.6
通讯作者：
Micheva,KristinaD
中科院分区：
文献类型：
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作者：
Simhal,AnishK;Zuo,Yi;Perez,MarcM;Madison,DanielV;Sapiro,Guillermo;Micheva,KristinaD
脆性X综合征（FXS）是一种常见的智力残疾遗传形式，已知会改变大脑皮层回路。然而，它对构成这些回路的不同突触类型的影响，或对星形胶质细胞的参与，尚不清楚。我们使用免疫荧光阵列断层扫描来量化FXS小鼠模型（FMR1敲除小鼠）成年体感皮层1至4层的不同突触群及其与星形胶质细胞的关系。收集的多通道数据包含约160万个突触，使用概率突触检测器对其进行分析。我们的研究揭示了FMR1基因敲除小鼠新皮质回路中复杂的突触型和层特异性变化。我们报道了第4层小的谷氨酸能VGluT1突触的增加，伴随着第1层和第4层大的VGluT1突触的减少。VGluT2突触在第1层和第2/3层显示出相当一致的密度下降。在所有层中，我们观察到大的抑制性突触的丢失。最后，兴奋性突触的星形细胞关联减少。通过突触类型和星形胶质细胞参与来解剖回路缺陷的能力对于理解这些变化如何影响回路功能，并最终确定治疗干预的目标至关重要。
Fragile X Syndrome (FXS), a common inheritable form of intellectual disability, is known to alter neocortical circuits. However, its impact on the diverse synapse types comprising these circuits, or on the involvement of astrocytes, is not well known. We used immunofluorescent array tomography to quantify different synaptic populations and their association with astrocytes in layers 1 through 4 of the adult somatosensory cortex of a FXS mouse model, the FMR1 knockout mouse. The collected multi-channel data contained approximately 1.6 million synapses which were analyzed using a probabilistic synapse detector. Our study reveals complex, synapse-type and layer specific changes in the neocortical circuitry of FMR1 knockout mice. We report an increase of small glutamatergic VGluT1 synapses in layer 4 accompanied by a decrease in large VGluT1 synapses in layers 1 and 4. VGluT2 synapses show a rather consistent decrease in density in layers 1 and 2/3. In all layers, we observe the loss of large inhibitory synapses. Lastly, astrocytic association of excitatory synapses decreases. The ability to dissect the circuit deficits by synapse type and astrocytic involvement will be crucial for understanding how these changes affect circuit function, and ultimately defining targets for therapeutic intervention.