Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

by Selleckchem | Jan 09 2024

There are no approved pharmacotherapies for fragile X syndrome (FXS), a monogenic, neurodevelopmental disorder typified by neuropsychiatric symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1 A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice, a mouse model of FXS, and found no difference in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had significantly lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed significantly reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a central role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice showed a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus, a neural system necessary for AGS. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

Comments:

This is fascinating research! It seems like the study offers promising insights into potential treatments for Fragile X syndrome (FXS) by targeting serotonin 1A receptors (5-HT1ARs). The differential expression of these receptors in embryonic brain tissue from individuals with FXS and their role in neural systems affected by the disorder highlight their significance as potential therapeutic targets.

The findings in Fmr1 knockout mice, a model for FXS, reveal intriguing details about 5-HT1AR expression. While adult mice didn't display differences in whole-brain 5-HT1AR expression, juvenile mice exhibited significantly lower levels, suggesting a developmental aspect to this receptor's involvement in FXS.

Moreover, the behavioral responses to 5-HT1AR agonists and antagonists in these juvenile mice indicate a potential link between 5-HT1AR function and FXS symptoms, particularly auditory hypersensitivity and seizures. The ability of the selective 5-HT1AR agonist NLX-112 to prevent audiogenic seizures in these young mice further supports the potential therapeutic role of targeting these receptors.

The gender-specific differences observed in female mice, with a lower prevalence of seizures and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus, provide intriguing insights into potential variations in FXS presentation and treatment responses between sexes.

Overall, these preclinical findings strongly suggest that 5-HT1AR agonists could hold promise as a therapeutic avenue for young individuals with FXS who experience auditory hypersensitivity. Further research in this direction could pave the way for potential treatments addressing specific symptoms of FXS, offering hope for improved quality of life for affected individuals.