Abstract
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.
Highlights
The unusually long and thin spines which are found in fixed tissues of Fragile X Syndrome (FXS) patients[9,10,17,18], are similar to the immature spines observed during development[19,20,21]
To better understand the synapse type-specific effects of FXS on the neocortical synaptic circuitry, we investigated the changes in different synaptic populations and their association with astrocytes in the adult mouse somatosensory cortex, an area in which a variety of deficits have been reported for FMR1 KO mice[37,38,39]
We focused on the superficial cortical layers where live-imaging studies have revealed changes in dendritic spine formation and turnover[37,40], but the synapse type specificity of the FXS effects is unknown
Summary
The unusually long and thin spines which are found in fixed tissues of FXS patients[9,10,17,18], are similar to the immature spines observed during development[19,20,21]. Astrocyte-specific deletion of FMR1 leads to significantly more immature spines in the mouse motor cortex due to overproduction of spines during development[36]. Whether such astrocytic contribution varies according to synapse type is not yet known. To better understand the synapse type-specific effects of FXS on the neocortical synaptic circuitry, we investigated the changes in different synaptic populations and their association with astrocytes in the adult mouse somatosensory cortex, an area in which a variety of deficits have been reported for FMR1 KO mice[37,38,39]. Our results reveal multifaceted changes in the composition and astrocytic involvement in the synaptic circuitry of the somatosensory cortex of adult FMR1 KO mice
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