Mouse model of dopamine transporter-associated parkinsonism and co-morbid psychiatric disease

Dysfunctional dopaminergic neurotransmission is implicated in several pathologies, including movement disorders such as parkinsonism and psychiatric diseases, suggesting overlapping pathological mechanisms. The dopamine transporter (DAT) is a key regulator of dopamine signalling and rare disease-associated DAT variants can cause psychiatric diseases and early-onset parkinsonism. However, the pathobiological processes that link DAT dysfunction to both parkinsonism and psychiatric symptoms are unknown. To investigate this, we developed a novel mouse disease model that expresses two mutations in DAT derived from a patient diagnosed with both Parkinsonism and ADHD. Phenotypic characterization of the mutant mice revealed impaired DAT function and major homeostatic changes, including increased ambient extracellular DA levels, decreased evoked DA release, and reduced expression of both tyrosine hydroxylase (TH) and of DA D1/D2 receptors. This was accompanied by diminished striatal dopaminergic axonal density and a psychomotor phenotype characterized by hyperactivity, enhanced exploratory activity, and pronounced clasping. Summarized, by replicating core aspects of the patient's phenotype, the mouse model provides insights into the mechanisms underlying the co-morbidity between neuropsychiatric diseases and Parkinsonism.