A Non-Canonical Role of Angiotensin-Converting Enzyme in Synaptic Plasticity

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A Non-Canonical Role of Angiotensin-Converting Enzyme in Synaptic Plasticity

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A diverse repertoire of endogenous opioid peptides are found within the brain, but because they are often co-expressed and co-released with other peptides, their role in synaptic plasticity remains elusive. These neuropeptides can have profound control over synaptic transmission upon binding to opioid receptors, particularly within the nucleus accumbens where converging signals are integrated to drive motivated behaviors. Neuropeptide effects are often terminated by extracellular degradation, but the mechanisms underlying this are also poorly understood. The identification of specific endogenous opioid peptides and insight into their extracellular regulation can reveal under-appreciated mechanisms that influence opioid receptor signaling to modulate the elaborate neuronal connectivity within this region. The studies presented in this dissertation show that an unconventional and potent endogenous opioid called Met-Enkephalin-Arg-Phe (“MERF”), an enkephalin heptapeptide, dose-dependently inhibited excitatory synaptic transmission onto medium spiny neurons (MSNs) in mouse brain slices. Angiotensin-converting enzyme (ACE) classically regulates blood pressure in the periphery and was found to non-canonically degrade endogenous MERF thereby regulating its effect in the nucleus accumbens. Liquid chromatography-tandem mass spectrometry analysis showed that a class of cardiovascular medications called ACE inhibitors selectively preserved extracellular MERF without affecting conventional enkephalins. ACE inhibitors alone unveiled cell type-specific depression of glutamate release onto MSNs expressing the Drd1 dopamine receptor (D1-MSNs), but not onto those expressing the Drd2 receptor (D2-MSNs). Glutamatergic synaptic depression was mediated by MERF binding to presynaptic µ-opioid receptors and was absent after conditional genetic deletion of ACE. Fiber photometry recordings of D1-MSNs in vivo demonstrated decreased sensitivity to optogenetic stimulation of excitatory medial prefrontal cortex following systemic administration of the ACE inhibitor captopril. Furthermore, mice given captopril displayed attenuated fentanyl-induced place preference and increased social behavior with other mice. Collectively, this dissertation defines an endogenous mechanism of synaptic plasticity induced by MERF and gated by ACE. We interpret this to be preclinical evidence for a class of safe and efficacious cardiovascular medications that could be repositioned or redesigned to mitigate brain conditions with underlying aberrant striatal pathophysiology characterized by an imbalance of D1- to D2-MSN synaptic activity.


University of Minnesota Ph.D. dissertation. June 2022. Major: Neuroscience. Advisor: Patrick Rothwell. 1 computer file (PDF); ix, 128 pages.

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Trieu, Brian. (2022). A Non-Canonical Role of Angiotensin-Converting Enzyme in Synaptic Plasticity. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241622.

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