Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability and a leading genetic contributor to autism spectrum disorders (ASDs). It is caused by the loss of Fragile X Mental Retardation Protein (FMRP), an mRNA-binding protein essential for synaptic function, plasticity, and neuronal development. While sensory processing abnormalities are a well-documented feature of FXS, the olfactory system remains an underexplored domain in both human studies and animal models. This review examines the structural and functional deficits in the olfactory system of FXS models, focusing on rodent and Drosophila studies that provide critical insights into the mechanisms underlying olfactory dysfunction. In Fmr1 knockout (KO) mice, structural abnormalities in the olfactory bulb, including aberrant dendritic morphology of mitral cells and increased granule cell spine density, lead to disruptions in excitatory/inhibitory (E/I) balance and impaired odor discrimination. Similarly, in Drosophila FXS models (dfmr1 mutants), synaptic connectivity deficits in the antennal lobe and mushroom body result in broadened odor tuning, reduced odor selectivity, and altered olfactory-guided behaviors. These deficits are linked to hyperexcitability and diminished GABAergic inhibition, mirroring findings in other sensory circuits affected by FXS. Although direct evidence of olfactory dysfunction in FXS patients is limited, ASD studies suggest that structural changes in the olfactory bulb and prefrontal cortex may contribute to sensory processing abnormalities in FXS as well. By combining findings from diverse model systems, this review highlights the olfactory system as a promising framework for understanding sensory processing deficits in FXS and their broader impact on neural function.

The integration of optogenetic techniques with traditional behavioral paradigms has provided novel insights into the neural mechanisms underlying olfactory-based fear conditioning. Olfactory cues are potent triggers for fear responses, and understanding the intricate neural dynamics involved in olfactory fear learning is crucial for unraveling the complexities of aversive memory formation. In this study, a robust method is presented that combines optogenetic stimulation of olfactory bulb glomeruli with foot shock fear conditioning to investigate olfactory-based fear learning in mice. By merging optogenetic manipulation with behavioral assays, a comprehensive framework for studying the mechanisms of olfactory fear conditioning is provided. This method offers new avenues for exploring the neural dynamics of adaptive responses to olfactory threats and may have implications for understanding fear-related disorders.