Olfactory Deficits in Fragile X Syndrome.

Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and a major genetic cause of autism spectrum disorders (ASDs). It results from the loss of fragile X mental retardation protein (FMRP), an mRNA-binding protein critical for synaptic development and plasticity. Although sensory processing abnormalities are well recognized in FXS, the olfactory system remains relatively underexplored in both human and animal studies. Evidence from rodent and drosophila models reveals that FMRP loss profoundly alters olfactory circuitry and function. In Fmr1 knockout mice, aberrant mitral cell dendritic morphology and increased granule cell spine density disrupt excitation/inhibition (E/I) balance, leading to circuit hyperexcitability and impaired odor discrimination. Similarly, dfmr1-deficient flies show reduced GABAergic inhibition, broadened odor tuning, and altered odor-guided behaviors, reflecting conserved mechanisms of synaptic dysregulation. These findings parallel disruptions seen in other sensory systems, underscoring the olfactory bulb as a microcircuit model for studying FXS-related neural dysfunction. Human evidence remains limited, but studies in ASD suggest that structural alterations in the olfactory bulb and prefrontal cortex may contribute to sensory deficits in FXS. Integrating findings across species, this review highlights the olfactory system as a translational framework for linking molecular dysfunction to circuit-level and behavioral abnormalities. By focusing on this well-characterized sensory network, it emphasizes how early synaptic and structural disruptions in FXS give rise to E/I imbalance and sensory processing impairments, providing insights into broader neurodevelopmental mechanisms and potential therapeutic targets.