Age-Related Decline in Dendritic Architecture of Hippocampal CA1 Principal Neurons in a Mouse Model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is associated with attention deficits, hyperactivity, anxiety, impulsivity, and repetitive behaviors. The disorder results from transcriptional silencing of the FMR1 gene, leading to loss of fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein that regulates local dendritic translation by repressing ribosomal activity. To examine how impaired local protein synthesis affects dendritic organization, we used Golgi–Cox staining to analyze hippocampal CA1 principal neurons across four developmental stages (P14–21, P30–40, P60–80, and P120–150) in an FXS mouse model. We identified a progressive reduction in dendritic complexity, reflected by decreased Sholl intersections and reduced dendritic branch number and length. In contrast, spine density was increased in both apical and basal dendrites during early development but normalized to wild-type levels in adulthood. Collectively, these structural alterations are likely to disrupt neural circuit development, with downstream consequences for cognition and behavior characteristic of FXS.