Evaluation of Medaka as an Animal Model to Study Autism Spectrum Disorder

Autism spectrum disorder (ASD) is an umbrella term used to define a broad spectrum of atypical social, cognitive and verbal behaviors along with repetitive and sometimes self-injurious actions. The behavioral criteria used to diagnose ASD are not sufficient to justify the diagnosis. Moreover, there is no appropriate medicine available for the treatment of ASD. Although the psychoactive drug risperidone is prescribed for ASD patients, the majority of them use alternative medicines for the prevention of this disorder. We predict that two major barriers exist in understanding the pathogenesis of ASD: (1) the absence of a defined phenotypic marker or gene product specific to ASD, and (2) the lack of an appropriate animal model that can display core symptoms of ASD. We are evaluating medaka as an animal model to identify exogenous phenotypic features of ASD using valproic acid (VPA) as the inducer. Our aims are to evaluate the efficacy of many natural products which are documented as potent inhibitor of ASD. Moreover, VPA is an inducer of fetal valproate syndrome (FVS) which is characterized by spina bifida, anencephaly and other developmental defects observed in cardiovascular, craniofacial, skeletal systems and limbs. We will differentiate ASD from FVS by using both phenotypic and genotypic analysis. Fertilized medaka eggs at specific phase of central nervous system development (1–3 day post fertilization, dpf) were exposed to different concentrations of VPA for 48 hours and the mortality was assessed on 10 dpf. The calculated IC₅₀ as determined on 10 dpf is 11±2 mM. The cardiovascular development is affected in medaka by VPA. The heartbeat rates were reduced significantly in embryos exposed to 5 and 10 mM of VPA but not in 2 mM VPA on 6, 7 and 8dpf. Further we are evaluating the modification of craniofacial cartilages in medaka hatchlings exposed to VPA during development. We predict that studies in craniofacial cartilage development and differentiation may be able to identify a unique phenotypic feature that can be able to differentiate ASD from FVS.

Acknowledgements: This research is supported in part by the United States Department of Agriculture, Agricultural Research Service, Specific Cooperative Agreement No 586408–2-0009. The project described was also supported by grant number 5P20RR021929 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.