FPT, a Novel 5‐HT₇ and 5‐HT_1A Partial Agonist, Treats Neuropsychiatric Symptoms Modeled in Fmr1 Knockout Mice

Abstract

Fragile X Syndrome (FXS) is the leading monogenetic cause of intellectual disabilities and autism. Seizures, severe anxiety, and sensory hypersensitivity are also common in FXS. The central serotonin system can modulate these symptoms, and certain serotonin receptors are functionally linked with proteins known to be altered in FXS, suggesting targeting them may be therapeutic for FXS. We are developing (S)‐5‐(2′‐Fluorophenyl)‐N, N‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine (FPT), a partial agonist at both 5‐HT7 and 5‐HT1A receptors, as a treatment for FXS and autism. We previously reported that FPT corrects repetitive behaviors and enhances social interactions—core symptom domains in FXS and autism—in wild‐type (WT) mouse models. Herein, we report the results of tests assessing the efficacy of FPT to improve behavioral phenotypes in Fmr1 knockout (KO) mice, an etiologically valid genetic model of FXS. Fmr1 KO mice have seizures when exposed to a 120 dB alarm (audiogenic seizures, AGS). 73% of vehicle‐treated Fmr1 KO mice we tested had AGS (males and females, age P23–25, N=22), however, 0% of the Fmr1 KO mice pretreated with FPT (5.6 mg/kg) had AGS (N=20). This effect was very significant (P<0.0001). In addition, FPT significantly reduced marble burying (vehicle, N=11, FPT, N=10, P<0.001) and reduced rearing in Fmr1 KO mice (vehicle, N=12, FPT, N=12, P<0.05). These data corroborate our earlier studies that FPT corrects repetitive behaviors and may have anxiolytic properties. We next tested FPT's efficacy to promote social behavior. Mice were matched for genotype and sex and paired together for a 10 minute observation period. One mouse was given vehicle and the other was given FPT. Social behavior, scored by an observer blind to treatment, was defined as the number of approaches from one mouse to the other and was recorded for each mouse within the pair. FPT increased social behavior in both WT (P<0.005) and Fmr1 KO (P<0.05) mice. We did not observe overt behavioral toxicity (for example, hypolocomotion, flat body posture, tremor, or head weaving) in mice treated with FPT. Our data provide further evidence that FPT has activity in neurobehavioral assays suggesting anxiolytic and prosocial effects that extend from WT to Fmr1 KO mice.Support or Funding InformationDOD W81XWH‐17‐1‐0329, FRAXA Research FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.