REGULATION OF DOPAMINE BY CELLS OF THE BLOOD-BRAIN BARRIER

Cells of the blood-brain barrier (BBB) including endothelial cells, mural cells and astrocytes prevent the entry of toxic blood-borne molecules into the brain while clearing waste metabolites including excess neurotransmitters from the brain. Dopamine is a neurotransmitter essential for the regulation of movement, reward, emotion, working memory and attention and its dysregulation is implicated in a wide range of neurological diseases. In Parkinson’s disease (PD), the degeneration of dopaminergic neurons leads to motor symptoms that can be managed with the dopamine precursor levodopa that unlike dopamine crosses the BBB. Surprisingly, the mechanisms by which the BBB transports levodopa and regulates dopamine levels in the brain are largely unknown. Using single-cell RNA sequencing, in-situ hybridization and immunohistochemistry, we found that the cerebral vasculature highly expresses the enzymes to produce and break down dopamine. Furthermore, we identified the expression of various potential transporters for levodopa. These transporters and enzymes were particularly enriched in a specialized subset of endothelial cells lining capillaries, which comprise the majority of the brain’s vasculature. In vivo pharmacology, genetic manipulations and two-photon imaging revealed that BBB endothelial cells play a crucial role in dopamine synthesis, breakdown and storage. By identifying non-neuronal mechanisms of dopamine control, this work may open up novel therapeutic avenues to restore brain dopamine levels in various neurological and psychiatric conditions.