Ultrastructure and morphometric analysis of hippocampal synapses in the Fmr1-/y mouse model of fragile X syndrome




Weiser Novak, Samuel

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Fragile X Syndrome (FXS) is a prevalent monogenic disease, often presenting with cognitive and neurological disorders including autism and epilepsy. The Fmr1 gene - transcriptionally silenced in FXS - normally encodes the Fragile X Mental Retardation Protein (FMRP), which acts as an activity dependent translational regulator at the base of dendritic spines. In an attempt to understand its role, dendritic spines in the dentate gyrus (DG) and cornu ammonis 1 (CA1) hippocampal regions of three-week old Fmr1- mice were analyzed and compared to wildtype (WT) littermate controls using electron microscopy. Dendritic spines with a continuous profile of the parent dendrite, spine neck, and spine head complete with synaptic components (presynaptic vesicles and postsynaptic densities) were included in our morphological analyses. We observed no changes in postsynaptic density length (DG: 5.69±0.30/6.18±0.85; SR: 7.55±0.87/6,96±0.33 µm/100 µm2; p=0.627/0.620), synapse density (DG: 32.3±3.8/30.3±1.9; SR: 34.4±1.8/30.7±0.5 synapses/100 µm2; p=0.655/0.270), spine head diameters (DG: 0.524±0.016/0.529±0.014; SR: 0.524±0.014/0.515±0.014 µm; p=0.098/0.20) or spine neck lengths (DG: 0.457±0.016/0.485±0.019; SR: 0.421 ± 0.015/0.425±0.017 µm; p=0.14/0.26), but found that in the DG spine necks were significantly narrower in the Fmr1- mice (0.193±0.0062/0.167±0.0064 µm; p=0.0002), whereas there were no changes in CA1 spine neck widths (0.162±0.0049/0.161±0.0061 µm; p=0.073). Estimated resistance calculated from spine necks morphologies revealed a ~1.7 fold increase in the Fmr1- DG compared to WT DG. These findings support that FMRP plays a role in granule cell spine neck structure and may influence synaptic signal compartmentalization and propagation in a regionally dependent manner.



neuroscience, fragile x syndrome, dendritic spines, electron microscopy