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


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.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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Mark C. Fishman studies the social behavior of zebrafish, focusing on the genetic, neuronal, and developmental aspects of group behavior.

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