Department of Electrical Engineering, Duke University, Durham, USA.
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, USA.
Sci Rep. 2019 Sep 25;9(1):13855. doi: 10.1038/s41598-019-50240-x.
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.
脆性 X 综合征（FXS）是一种常见的遗传性智力障碍，已知其会改变新皮层回路。然而，其对组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情况，尚不清楚。我们使用免疫荧光阵列断层扫描技术，在脆性 X 综合征的小鼠模型，即 FMR1 敲除小鼠的成年体感皮层 1 至 4 层中，定量研究不同的突触群及其与星形胶质细胞的关联。所收集的多通道数据包含大约 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 敲除小鼠新皮层回路中复杂的、突触类型和层特异性的变化。我们报告说，在 4 层中小谷氨酸能 VGluT1 突触增加，而在 1 层和 4 层中大 VGluT1 突触减少。在所有层中，我们观察到密度一致降低的 VGluT2 突触。在所有层中，我们观察到大抑制性突触的丧失。最后，兴奋性突触与星形胶质细胞的关联减少。通过突触类型和星形胶质细胞参与来剖析回路缺陷的能力，对于理解这些变化如何影响回路功能，以及最终确定治疗干预的目标至关重要。
