Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine

• Published in: iScience 2019-07, Vol.17, p.325-333
• Main Authors: Wang, Guangliang, Zhang, Guoqiang, Li, Zhuyun, Fawcett, Caroline H., Coble, Matthew, Sosa, Maria X., Tsai, Tingwei, Malesky, Kimberly, Thibodeaux, Stefan J., Zhu, Peixin, Glass, David J., Fishman, Mark C.
• Format: Article
• Language: English
• Subjects: Behavioral Neuroscience; Biological Sciences; Ethology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.06.039

Dopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3−/− fish hover near the tank bottom, with a repetitive digging-like behavior. slc6a3−/− fish manifest pruning and cellular loss of particular tyrosine hydroxylase-immunoreactive neurons in the midbrain. Clozapine, an effective therapeutic for treatment-resistant schizophrenia, rescues the abnormal behavior of slc6a3−/− fish. Clozapine also reverses the abnormalities in the A8 region of the mutant midbrain. By RNA sequencing analysis, clozapine increases the expression of erythropoietin pathway genes. Transgenic over-expression of erythropoietin in neurons of slc6a3−/− fish partially rescues the mutant behavior, suggesting a potential mechanistic basis for clozapine's efficacy. [Display omitted] •DAT mutation in zebrafish causes digging behavior and loss of specific midbrain neurons•Clozapine restores normal behavior and neuronal morphology of mutant fish•Clozapine increases expression of erythropoietin pathway genes•Transgenic expression of erythropoietin partially rescues the mutant behavior Biological Sciences; Ethology; Behavioral Neuroscience