Expression of Angiotensin converting enzyme 2 (ACE2) in the dorsolateral striatum is critical for the temporal coordination of acetylcholine and dopamine, and motor learning.

Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine-tuning fast neurotransmitter action under physiological conditions. We found that the mono-carboxypeptidase angiotensin-converting enzyme 2 (ACE2), which can take part in producing and/or processing of several neuroactive peptides in the mammalian brain and is best known for converting the pro-inflammatory peptide angiotensin II (Ang II) to the stress-ameliorating and neuro-protective peptide angiotensin 1–7 (Ang 1–7), is broadly expressed in the striatum. Cholinergic interneurons (CIN) of the striatum, known to express multiple peptide receptors also co-expressed the corresponding and functionally opposing receptors angiotensin type 1 receptor (AT1R) for Ang II and mas receptor (MasR) for Ang 1–7 . Accordingly, the conditional, semi acute ablation and/or local pharmacological inhibition of ACE2 increased the frequency of acetylcholine (ACh) bursts, reduced the amplitude of dopamine (DA)-modulated pausing of CIN activity, and disrupted the temporal coordination of extracellular levels of ACh and DA during burst events. Further, ablation of ACE2 in the DLS biased directional movement and impaired motor skill learning. Co-injection of the AT1R inhibitor losartan and the dopamine D2 receptor (D2R) agonist quinpirole reduced steady state level cholinergic activity in an additive manner, and proximity ligation supported close spatial association of AT1R and D2R on CINs. Together our study provides evidence that striatal produced ACE2 impinges on the dynamics of ACh and DA and impacts action selection and motor learning through functional and structural interactions of peptidergic and dopaminergic signaling on CIN.