Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD

Freja Herborg; Lisa K. Konrad; Søren H. Jørgensen; Jamila H. Lilja; Benoît Delignat-Lavaud; Leonie P. Posselt; Ciara F. Pugh; Sofie A. Bach; Cecilia F. Ratner; Nora Awadallah; Jose A. Pino; Frida Berlin; Aske L. Ejdrup; Mikkel V. Olesen; Mattias Rickhag; Birgitte Holst; Susana Aznar; Felix P. Mayer; David Woldbye; Gonzalo E. Torres; Louis-Eric Trudeau; Ulrik Gether

doi:10.1172/JCI169297

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Rickhag, M. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Holst, B. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Aznar, S. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Mayer, F. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Woldbye, D. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Torres, G. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Find articles by Trudeau, L. in: PubMed | Google Scholar

¹Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

²CNS Research Group, Department of Pharmacology and Physiology, Department o, University of Montreal, Montreal, Canada

³Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

⁴Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine at City College, New York, United States of America

⁵Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Universidad Viña del Mar, Valparaíso, Chile

⁶Centre for Neuroscience and Stereology, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

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J Clin Invest. https://doi.org/10.1172/JCI169297.
Copyright © 2026, Herborg et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published January 27, 2026 - Version history

Atypical dopamine transporter (DAT) deficiency syndrome (DTDS) arises from genetic disruption of DAT function and is characterized by early-onset parkinsonism alongside comorbid psychiatric symptoms. However, the underlying pathobiological processes are largely unknown. Here, we present a mouse model of atypical DTDS based on the patient-derived compound heterozygote genotype, DAT-I312F/D421N^+/+. DAT-I312F/D421N^+/+ mice exhibited markedly impaired DAT function, leading to widespread changes in dopamine homeostasis, including elevated extracellular dopamine levels, reduced tyrosine hydroxylase and dopamine D1/D2 receptor expression, and decreased evoked dopamine release, mechanistically linked to enhanced tonic D2 autoreceptor inhibition. Fiber photometry measurements revealed disrupted fast striatal dopamine release dynamics, while confocal imaging showed reduced striatal dopaminergic axon fiber density. These neurochemical changes were accompanied by a psychomotor phenotype characterized by hyperlocomotion, enhanced exploration and pronounced clasping. Both amphetamine and anticholinergic treatment ameliorated the aberrant hyperactivity. Notably, amphetamine-induced dopamine release was profoundly blunted in ventral striatum but largely preserved in dorsal striatum, implicating region-specific dopamine release dynamics as a determinant of divergent behavioral and pharmacological responses. Summarized, our findings uncover multiscale dopamine dysfunction that links presynaptic DAT impairment to synaptic and circuit-level disruptions, offering insight into atypical DTDS and the co-occurrence of movement and psychiatric features.

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Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD

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