Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.
Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Copenhagen, DK · Author affiliation
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Location evidence
Montréal, CA · Author affiliation
CNS Research Group, Department of Pharmacology and Physiology, Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada.Location evidence
Québec, CA · Author affiliation
CNS Research Group, Department of Pharmacology and Physiology, Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada.Location evidence
New York City, US · Author affiliation
Department of Molecular, Cellular, and Biomedical Sciences, City University of New York School of Medicine, New York, New York, USA.Location evidence
Viña del Mar, CL · Author affiliation
Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Facultad de Ciencias de la Vida, Universidad Viña del Mar, Valparaíso, Chile.Location evidence
Valparaíso, CL · Author affiliation
Laboratorio de Bioquímica y Farmacología Molecular, Escuela de Ciencias, Facultad de Ciencias de la Vida, Universidad Viña del Mar, Valparaíso, Chile.Location evidence
Hvidovre, DK · Author affiliation
Danish Research Centre for Magnetic Resonance (DRCMR), Department of Radiology and Nuclear Medicine, Copenhagen University Hospital-Amager and Hvidovre, Copenhagen, Denmark.Location evidence
Chicago, US · Author affiliation
Department of Molecular Pharmacology and Neuroscience, Stritch School of Medicine, Loyola University, Chicago, USA.Location evidence
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Original abstract
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.