Fragile X syndrome (FXS), the most common known cause of autism, is caused by mutations in a single gene, FMR1. Loss of FMR1 leads to a variety of symptoms that are prevalent across many autism-spectrum disorders including social and communication impairments, intellectual disability, and an extreme sensitivity to sensory stimuli, thought to be a major contributor to patients’ anxiety. Hypersensitivity is thought to reflect changes in the brain rather than in the peripheral nervous system. We are studying the basis for hypersensitivity to odor, a key contributor to restricted food choice in FXS patients, using a mouse model of FXS. To understand whether smells are processed differently in Fmr1 null mice, we are investigating whether there is a change neuronal activation in response to odors in several important olfactory processing regions. Surprisingly, we found an increased response to odors in the peripheral olfactory system of Fmr1 null mice compared to wild type mice. This increased response did not reflect a change in the overall number of olfactory sensory neurons and correlated with an enhanced peripheral odor response as measured using electrophysiology. We are currently investigating if the increased peripheral activation propagates to olfactory processing units in the brain. Our observations suggest a novel phenomenon where sensory hypersensitivity arises from a disordered response to stimuli in the peripheral nervous system in addition to impaired processing in the brain, with implications for new therapeutic targets.
