The selective 5-HT1A receptor biased agonist, NLX-101, corrects anomalous behavioral phenotype in a mouse model of Fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the most prevalent X-linked dominant autism spectrum disorder, causing a range of developmental problems, notably characterized by mild to severe mood/cognitive dysfunctions. NLX-101 is a highly selective and fully efficacious biased agonist at post-synaptic 5-HT1A receptors, and has shown efficacy for reversal of sensory hypersensitivity and EEG anomalies in transgenic mouse models of FXS. Presently, we examined the ability of NLX-101 to normalize several aspects of behavioral anomalies displayed by adult male FMR1 KO2 mice, a transgenic murine model of FXS. FMR1 KO2 mice were treated with NLX-101 (0.64 & 2.5 mg/kg intraperitoneally) and tested sequentially in 1) the open-field test to study hyperactivity and stereotypies (self-grooming), 2) the three chamber partition test (social memory), 3) the nesting behavior test (daily living), 4) the novel object recognition test (working memory) and 5) the hyponeophagia (novelty suppression feeding) test (anxiety). Each test was separated by a three-day wash-out period. NLX-101 normalized hyperactivity and excessive self-grooming at both 0.64 and 2.5 mg/kg, whereas hyponeophagia, and deficits in working and social memory, were partially normalized at 0.64 mg/kg and fully at 2.5 mg/kg. Abnormal nest building was partially normalized at 2.5 mg/kg. In conclusion, NLX-101 exerts beneficial and dose-dependent activity against several behavioral and mood/cognitive deficits displayed by FMR1 KO2 mice. These results highlight the therapeutic potential of using a selective post-synaptic 5-HT1A receptor biased agonist as a novel strategy to treat FXS, for which there is currently no approved efficacious and safe pharmacotherapy. SUMMARYO_LIFragile X syndrome (FXS) is the most prevalent X-linked dominant autism spectrum disorder. C_LIO_LINLX-101, a highly selective serotonin 5-HT1A receptor agonist, was previously shown to reverse sensory hypersensitivity and brain electrical activity anomalies in a gene knock-out (FMR1 KO) mouse model of FXS. C_LIO_LIHere, NLX-101 corrected the anomalous behaviors (hyperactivity, stereotypies, anxiety, deficient social and working memories and nesting behavior) of FMR1 KO2 mice. C_LIO_LITreatment with a selective 5-HT1A receptor agonist such as NLX-101 could represent a promising strategy to treat cognitive and behavioral disturbance in FXS. C_LI