Hidden Players in Sensory Deficits: ‘Dark’ Odorant Receptors in the Fragile X Syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2025.

The sense of smell, or olfaction, is vital for perceiving the world and adapting to the environment. It shapes behavior by processing odors, and disruptions can lead to sensory deficits, impaired social interactions, and reduced quality of life. Among the different senses, olfaction is crucial across species. In vertebrates, most odorants are detected by olfactory receptors (ORs), expressed in the cilia of the olfactory sensory neurons (OSNs). The sense of smell begins when odorant molecules bind to odorant receptors (ORs) in the olfactory epithelium (OE), which then sends signals to the brain, ultimately leading to the modulation and refinement of neuronal circuitry. Many of these receptors belong to a group of genes known as ‘dark genes,’ a class of genes that are poorly understood and not well characterized. Fragile X Syndrome (FXS) is a genetic disorder associated with social and sensory issues, including in both humans and mouse models, difficulties in odor perception. Compared to wild-type mice, FXS animal models show olfactory processing behaviors and difference in the structure of different components of the olfactory system. Yet, olfactory dysfunctions are still largely under-investigated in FXS, and the molecular mechanisms of such dysfunctions are completely unknown. We hypothesize that ORs, because of their crucial role in processing olfactory cues, are affected in FXS and causative of the documented sensory dysfunctions. Our goal is to evaluate the role of a group of 'Tdark genes' encoding for olfactory receptors. Identifying the deregulated odorant receptors may enable us to pinpoint specific odorants that could interact with and modulate neuronal responses and behavior in rodents and in the future in humans. Our research therefore could identify new molecular targets for potential diagnostic and/or treatments that may ultimately improve the quality of life for individuals affected by FXS.