Dendritic Spine Ultrastructure in Fragile X syndrome: Evidence for Narrower Neck Widths in Dentate Gyrus Granule Cell Neurons of the Hippocampus

Abstract

Fragile X Syndrome (FXS) is a prevalent monogenic disease that presents neurological abnormalities including learning/memory deficits, autism and epilepsy. The Fmr1 gene ‐ transcriptionally silenced in FXS ‐ normally encodes the Fragile X Mental Retardation Protein (FMRP), of which its function is still obscure, but has been shown to localize at dendritic spines of cortical neurons. In an attempt to understand its role, dendritic spines in the dentate gyrus (DG) and cornu ammonis 1 (CA1) hippocampal regions of 21 day FMRP knockout (KO) mice were analyzed and compared to wildtype (WT) littermate controls using electron microscopy. Spines continuous with a parent dendrite were only included in our analyses. There were no significant differences in spine head diameters (DG: 0.529 ±0.014 vs 0.524 ±0.016; CA1: 0.515 ±0.014 vs 0.524 ±0.014µm), postsynaptic density lengths (DG: 6.18 ±0.85 vs 5.69 ±0.30; CA1: 7.55 ±0.87 vs 6.96 ±0.33µm/100µm2) or spine neck lengths (DG: 0.485 ±0.019 vs 0.457 ±0.016; CA1: 0.425 ±0.017 vs 0.421 ±0.015µm) in KO vs WT mice. Spine neck diameters, however, were significantly narrower in the DG of FMRP KO mice (0.193 ±0.0062 vs 0.167 ±0.0064µm) whereas no significant differences were observed in the CA1 (0.162 ±0.0049 vs 0.161 ±0.0061µm). Estimated resistance provided by narrower spine necks in the DG revealed a ~1.7 fold increase in the resistivity of spines. Taken together, these findings suggest that FMRP plays a role in granule cell neuron spine neck structure and may influence signal propagation in a regionally‐specific manner in the hippocampus.