Angiotensin-converting enzyme gates brain circuit–specific plasticity via an endogenous opioid

Title: Angiotensin-converting enzyme gates brain circuit–specific plasticity via an endogenous opioid

Journal: Science(2022) 375(6585):1177-1182

Link: https://doi.org/10.1126/science.abl5130

Comments: Angiotensin-converting enzyme (ACE) plays a vital role in regulating blood pressure via cleaving angiotensin I to generate angiotensin II which directly stimulates vasoconstriction of blood vessels. ACE is expressed in brain tissue, especially in striatal tissue, but the main function in the brain is still unclear. The group comes from University of Minnesota Medical School identified that ACE cleaves and degrades Met-enkephalin-Arg-Phe(MEAP), an unconventional enkephalin, which has the capacity to enhance μ-opioid receptor activation in the nucleus accumbens. It turns out that ACE has a noncanonical role in governing endogenous opioid signaling in the brain. These findings may explain the antidepressant effects of ACE inhibitor.

Multiple brain disorders involve imbalanced output of nucleus accumbens (NAc) medium spiny projection neurons expressing dopamine receptor Drd1(D1-MSNs) or Drd2 (D2-MSNs). ACE is expressed abundantly in the dorsal striatum and NAc by D1-MSNs. Inhibitors of ACE and other peptidases can be combined to regulate striatal excitatory synaptic transmission in an opioid-dependent fashion. The author applied whole-cell recordings in acute NAc brain slices from double-transgenic Drd1-tdTomato/Drd2-eGFP reporter mice in order to determining how ACE inhibition affects excitatory synaptic transmission onto D1-MSNs and D2-MSN respectively. The results have shown that ACE inhibition reduces excitatory input to D1-MSNs via endogenous opioid signaling. They further verified that ACE selectively degrades MERF in the extracellular space. Data measured by miniature excitatory postsynaptic currents indicated captopril, an ACE inhibitor, enhances MERF effects on presynaptic and postsynaptic opioid receptors. Experiments performed by fiber photometry in vivo and unbiased place-conditioning assay demonstrated systemic captopril reduces excitatory input to D1-MSNs, counteracts fentanyl reward, and increases sociability. Collectively, the author claimed these evidence suggest central ACE inhibition could have therapeutic potential for a variety of brain conditions.