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

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.

Generation of the Human Pluripotent Stem-Cell-Derived Astrocyte Model with Forebrain Identity

“…Therefore, the present culture system might be particularly well suited for the research of neurodevelopmental disorders both as pure astrocyte as well as in co-culture assays. Astrocytes contribute to impaired neuronal function in many neurodevelopmental disorders [ 59 , 60 , 61 ] and patient-derived astrocyte models can make a significant contribution to studies of human brain function.…”

Astrocytes in rare neurological conditions: Morphological and functional considerations

“…This protein is a translational repressor that is expressed in both neurons and astrocytes and is vital for normal synaptic transmission between neurons. Many studies on FXS have been conducted to look at the functional role of astrocytes in various processes including synaptic development, synaptic transmission, and dendritic spine morphology (Ariza et al, 2017;Cheng et al, 2012;Simhal et al, 2019). Simhal et al (2019) recently conducted a study in a mice model of FXS to identify the role of astrocytes in synaptic composition.…”

“…Many studies on FXS have been conducted to look at the functional role of astrocytes in various processes including synaptic development, synaptic transmission, and dendritic spine morphology (Ariza et al, 2017;Cheng et al, 2012;Simhal et al, 2019). Simhal et al (2019) recently conducted a study in a mice model of FXS to identify the role of astrocytes in synaptic composition. Via immunofluorescent array tomography, they found that in FMRP knockout (KO) mice, there was a significant reduction in the density and amount of excitatory glutamatergic synapses that were associated with the processes of an astrocyte, suggesting that astrocytes have a diminished functional role in the modulation of excitatory synaptic transmission in FXS, consistent with the findings of other similar studies (Jawaid et al, 2018;Simhal et al, 2019).…”

“…Simhal et al (2019) recently conducted a study in a mice model of FXS to identify the role of astrocytes in synaptic composition. Via immunofluorescent array tomography, they found that in FMRP knockout (KO) mice, there was a significant reduction in the density and amount of excitatory glutamatergic synapses that were associated with the processes of an astrocyte, suggesting that astrocytes have a diminished functional role in the modulation of excitatory synaptic transmission in FXS, consistent with the findings of other similar studies (Jawaid et al, 2018;Simhal et al, 2019). In addition to changes in excitatory synapse density, astrocytes have been shown in FMRP KO FXS models to have aberrant secretion of various proteins and gliotransmitters, including interleukin-6 (IL-6), hevin, SPARC proteins, GABA, glutamate, and thrombospondin-1 which have all been shown to regulate excitatory synapse development and transmission (Cheng et al, 2016;Krasovska & Doering, 2018;Risher et al, 2014;S.…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…However, recent studies have identified previously unknown features of glial cells that facilitate their interaction with neurons during brain development, such as the release of gliotransmitters and cytokines. In addition, synaptic changes induced by glial cells in the developmental stage, including synaptic patterning secondary to pruning, are now being investigated in relation to the neuron-glia interactions [ 4 , 5 ]. Glial cells release gliotransmitters such as gamma-aminobutyric acid (GABA), glutamate, and cytokines [ 6 , 7 ], which may affect neurons both directly and indirectly [ 8 ].…”