Abstract
There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT(1A)Rs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT(1A)Rs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT(1A)Rs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT(1A)R densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT(1A)R expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT(1A)R expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT(1A)R agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT(1A)R antagonist, WAY-100635. Also, treatment with the selective 5-HT(1A)R agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT(1A)Rs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT(1A)Rs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT(1A)R agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.