August 1, 2025Open Access

α6GABAA RECEPTOR-SELECTIVE POSITIVE ALLOSTERIC MODULATOR AS A POTENTIAL THERAPY FOR AUTISM: A PRECLINICAL STUDY IN FMR1 KO MICE

YLYoung Ho LeeKorea University DSDishary SharminUniversity of Wisconsin–Milwaukee JCJames M. CookLung Institute

Key Points

DK treatment improved sociability and social preference in Fmr1 KO mice, demonstrating therapeutic potential for autism.
Fmr1 KO mice displayed significant social impairments, with male hemizygous mice showing more severe deficits than females.
Assessment used three-chamber social interaction test on juvenile mice at 5-6 weeks, finding treatment benefits across genotypes.
Results support DK's action on α6GABAARs, suggesting further investigation for ASD treatment is warranted.

Abstract

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with both genetic and environmental contribution risk factors. Our previous study has demonstrated that DK-I-56-1 (DK), a positive allosteric modulator (PAM) selective to the α6 subunit-containing GABAA receptors (α6GABAARs) can prevent the development of ASD-like core symptoms in prenatal valproic acid-exposure juvenile rats (accompanied presentation), representing the impact of environmental factors on ASD. Aims & Objectives In this study, we utilized the Fmr1 knockout (KO) (Fmr1 KO) mouse model, a preclinical ASD model representing the genetic impact in the pathogenesis of ASD, for screening potential therapy, to validate our hypothesis that α6GABAARs can enhance GABAergic transmission in granule cells (GCs) and restore Purkinje cell (PC) activity in the cerebellum and then mitigate ASD-like symptoms. Method The Fmr1 gene is an X-linked risk gene of ASD. We thus employed male hemizygotes (Fmr1-/y), as well as female hemizygotes (Fmr1-/+) and female homozygotes (Fmr1 -/-), using their wildtype littermates of the same sex as the Control groups. Juvenile mice at 5-6 weeks of age received the three-chamber social interaction test to assess their sociability and social preference. DK (10 mg/kg) or vehicle (Veh) was i.p. administered five days and 30 min before the three-chamber test on the tested day. Results Results showed a gene-dose effect where male hemizygous Fmr1 KO mice exhibited more severe deficits in sociability than female Fmr1 KO mice. Among females, homozygous Fmr1 KO mice showed greater impairments in both social preference and sociability than hemizygous counterparts. DK treatment (10 mg/kg, i.p.) pretreatment rescued social impairments across genotypes and sex. Discussion & Conclusions These therapeutic effects are consistent with DK’s action on α6GABAARs in the cerebellum. With favorable pharmacokinetics, including good oral bioavailability, a 13-hour half-life, and no sedative or abuse potential, DK is a promising candidate for treating ASD.1

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