Multifaceted Changes in Synaptic Composition and Astrocytic Involvement in a Mouse Model of Fragile X Syndrome

• Published in: Scientific reports 2019-09, Vol.9 (1), p.13855-16, Article 13855
• Main Authors: Simhal, Anish K., Zuo, Yi, Perez, Marc M., Madison, Daniel V., Sapiro, Guillermo, Micheva, Kristina D.
• Format: Article
• Language: English
• Subjects: 14/1; 14/63; 631/378/116; 631/378/1689; Animals; Astrocytes; Astrocytes - pathology; Brain - diagnostic imaging; Brain - pathology; Brain - physiopathology; Circuits; Disease Models, Animal; Female; Fluorescent Antibody Technique - methods; FMR1 protein; Fragile X syndrome; Fragile X Syndrome - pathology; Functional Neuroimaging; Glutamatergic transmission; Humanities and Social Sciences; Intellectual disabilities; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Rodents; Science; Science (multidisciplinary); Somatosensory cortex; Somatosensory Cortex - pathology; Somatosensory Cortex - physiopathology; Synapses; Synapses - pathology; Synapses - physiology; Tomography - methods; Vesicular Glutamate Transport Protein 1 - metabolism; Vesicular Glutamate Transport Protein 2 - metabolism
• ISSN: 2045-2322; 2045-2322
• 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.