Wang G, Zhang G, Li Z, Fawcett CH, Coble M, Sosa MX, Tsai T, Malesky K, Thibodeaux SJ, Zhu P, Glass DJ, Fishman MC. Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine. iScience. 2019 Jul 26; 17:325-333.

Citation

Wang G, Zhang G, Li Z, Fawcett CH, Coble M, Sosa MX, Tsai T, Malesky K, Thibodeaux SJ, Zhu P, Glass DJ, Fishman MC. 2019. Abnormal Behavior of Zebrafish Mutant in Dopamine Transporter Is Rescued by Clozapine. iScience. 17:325-333. Pubmed: 31325771 DOI:S2589-0042(19)30222-6

Abstract

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.

Related Faculty

Mark C. Fishman, M.D.

Fishman Lab

Mark C. Fishman’s group studies the heart-brain connection. They employ a range of genetic, developmental, and neurobiological tools in zebrafish to understand what the heart tells the brain, and how critical internal sensory systems adjust homeostatic and somatic behaviors, including social interactions.