5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

Abstract

Background Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-HT5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS. Methods We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (PPI; 0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (NORT; 0.1 mg/kg) in Frmr1-knockout (KO) rats. Results Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03–0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment. Conclusions ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Multi-level profiling of the Fmr1 KO rat unveils altered behavioral traits along with aberrant glutamatergic function

“…Noteworthy, both WT and KO rats demonstrated reduced levels of motor activity due to the longer exposure and subsequent familiarity with the open-field apparatus. In agreement with our results, increased motor activity as deduced by the total time spent in the open-field apparatus was observed for Fmr1 KO compared to WT rats [ 38 , 39 ]. Another study [ 40 ] reported that KO rats were hyperactive, only during the first recording interval.…”

“…Regarding recognition learning and memory, our results agree with other studies showing deficits in the novel object recognition test [ 39 , 45 – 47 ] and the novel location recognition task [ 48 ], however, one study did not report impairments in recognition and spatial memory [ 49 ].…”

FMR1 deletion in rats induces hyperactivity with no changes in striatal dopamine transporter availability

“…Moreover, investigating possible DA-independent mechanisms that may drive hyperactivity in Fmr1-Δ exon 8 rats also remains an intriguing point that deserves further investigation. For instance, the pharmacological targeting of serotonin 89,90 , GABA 91,92 , BDNF 93,94 , acetylcholine 95 pathways (to mention a few) has been demonstrated to ameliorate abnormal locomotor behaviors in Fmr1-KO mice. Despite dopaminergic aberrations have been extensively documented in Fmr1-KO mice 63,[96][97][98][99] , preclinical data on the striatal DAT activity remain controversial, with some studies reporting a decreased striatal DAT expression 97 , whereas others (including the present results) showing no change in DAT function 99 .…”