Ropinirole and pramipexole promote structural plasticity in human iPSC- derived dopaminergic neurons via BDNF and mTOR signaling

Ropinirole and pramipexole are D3 receptor (D3R)-preferring dopaminergic (DA) agonists used for the symptomatic, “DA-replacement” treatment of Parkinson’s disease. They likewise possess antidepressant properties and, while the exact mechanism of action remains uncertain, a role for restoration of impaired neuroplasticity has been proposed. Since D3R are highly expressed on DA neurons in humans, we evaluated their participation in the influence of ropinirole and pramipexole on structural plasticity using a translational model of human inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084. Visualization of phosphorylated p70S6 kinase indicated the recruitment of the mTOR pathway, critically involved in neuroplasticity. Phosphorylation of p70S6 kinase and structural plasticity were blocked by the kinase inhibitors LY294002 and rapamycin, confirming involvement of the mTOR pathway. Immunoneutralisation of BDNF, inhibition of TrkB receptors and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity. Similar results were obtained with pramipexole. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpins their reliability for characterization of agents acting via dopaminergic mechanisms. The present studies show that BDNF- and mTOR-driven signaling underlie the influence of ropinirole and pramipexole on the neuroplasticity of DA neurons. These actions may play an important role in their influence on DA-dependent functions like mood and motor function, known to be disrupted in several clinical disorders.