Fragile X syndrome (FXS) is a neurodevelopmental disorder and the leading known geneticcause of autism, resulting from the mutation of the Fmr1 gene which leads to a lack ofproduction of Fragile X Messenger Ribonucleoprotein (FMRP), a key protein in neuronaldevelopment and maintenance. This lack of FMRP results in cognitive deficiencies and sensoryprocessing issues, notably auditory sensitivity which, in its most robust presentation, can induceseizures upon exposure to intense stimulus: Audiogenic seizures (AGS). Previous studies inFmr1 knock-out mice demonstrated that administering NLX-101–a postsynaptic serotonin 1A(5HT1A) agonist reduced AGS. To determine if the specificity of NLX-101 is necessary forreducing AGS, we tested two drugs that more broadly modulate serotonin activity: 8-OH-DPAT,a less specific serotonin 1A agonist that also acts on presynaptic receptors, and Fluoxetine, aserotonin reuptake inhibitor (SSRI) which broadly and non-specifically increases serotoninactivity throughout the brain. Through exposing groups of combined drug-treated and untreatedFmr1 knockout mice to a loud (100-110 dB) modulating sound capable of triggering AGS inuntreated knockout mice, we found no significant differences in the severity of or the latency ofonset for AGS between untreated and drug-treated mice in both 8-OH-DPAT and Fluoxetinetreatments. Our findings indicate that the unique specificity of NLX-101 in modulating serotoninactivity due to only targeting postsynaptic 5-HT1A receptors is necessary to reduce AGS. Theseresults suggest the use of NLX-101, and other specific 5HT1A receptor agonists, as a therapeuticavenue to treat sensory hypersensitivity in FXS and other autisms.
