1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          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.

          Graphical Abstract

          Highlights

          • 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

          Abstract

          Biological Sciences; Ethology; Behavioral Neuroscience

          Related collections

          Most cited references26

          • Record: found
          • Abstract: found
          • Article: not found

          JAABA: interactive machine learning for automatic annotation of animal behavior.

          We present a machine learning-based system for automatically computing interpretable, quantitative measures of animal behavior. Through our interactive system, users encode their intuition about behavior by annotating a small set of video frames. These manual labels are converted into classifiers that can automatically annotate behaviors in screen-scale data sets. Our general-purpose system can create a variety of accurate individual and social behavior classifiers for different organisms, including mice and adult and larval Drosophila.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            How to make a midbrain dopaminergic neuron.

            Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study

              Summary Background Dopamine transporter deficiency syndrome is the first identified parkinsonian disorder caused by genetic alterations of the dopamine transporter. We describe a cohort of children with mutations in the gene encoding the dopamine transporter (SLC6A3) with the aim to improve clinical and molecular characterisation, reduce diagnostic delay and misdiagnosis, and provide insights into the pathophysiological mechanisms. Methods 11 children with a biochemical profile suggestive of dopamine transporter deficiency syndrome were enrolled from seven paediatric neurology centres in the UK, Germany, and the USA from February, 2009, and studied until June, 2010. The syndrome was characterised by detailed clinical phenotyping, biochemical and neuroradiological studies, and SLC6A3 mutation analysis. Mutant constructs of human dopamine transporter were used for in-vitro functional analysis of dopamine uptake and cocaine-analogue binding. Findings Children presented in infancy (median age 2·5 months, range 0·5–7) with either hyperkinesia (n=5), parkinsonism (n=4), or a mixed hyperkinetic and hypokinetic movement disorder (n=2). Seven children had been initially misdiagnosed with cerebral palsy. During childhood, patients developed severe parkinsonism-dystonia associated with an eye movement disorder and pyramidal tract features. All children had raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid in cerebrospinal fluid, of range 5·0–13·2 (normal range 1·3–4·0). Homozygous or compound heterozygous SLC6A3 mutations were detected in all cases. Loss of function in all missense variants was recorded from in-vitro functional studies, and was supported by the findings of single photon emission CT DaTSCAN imaging in one patient, which showed complete loss of dopamine transporter activity in the basal nuclei. Interpretation Dopamine transporter deficiency syndrome is a newly recognised, autosomal recessive disorder related to impaired dopamine transporter function. Careful characterisation of patients with this disorder should provide novel insights into the complex role of dopamine homoeostasis in human disease, and understanding of the pathophysiology could help to drive drug development. Funding Birmingham Children's Hospital Research Foundation, Birth Defects Foundation Newlife, Action Medical Research, US National Institutes of Health, Wellchild, and the Wellcome Trust.
                Bookmark

                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                04 July 2019
                26 July 2019
                04 July 2019
                : 17
                : 325-333
                Affiliations
                [1 ]Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
                [2 ]Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
                Author notes
                []Corresponding author mark_fishman@ 123456harvard.edu
                [3]

                Lead Contact

                Article
                S2589-0042(19)30222-6
                10.1016/j.isci.2019.06.039
                6642228
                31325771
                2cf02bb7-6b88-4c50-9868-8687a89b25df
                © 2019 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 8 March 2019
                : 17 May 2019
                : 28 June 2019
                Categories
                Article

                biological sciences,ethology,behavioral neuroscience

                Comments

                Comment on this article