Redefining differential roles of MAO-A in dopamine degradation and MAO-B in tonic GABA synthesis

Hyun-U Cho,Min-Ho Nam,Jeongeun Sim,C Justin Lee,Heeyoung An,Dong-Pyo Jang,Sunpil Kim,Seulkee Yang

doi:10.1038/s12276-021-00646-3

Abstract

Monoamine oxidase (MAO) is believed to mediate the degradation of monoamine neurotransmitters, including dopamine, in the brain. Between the two types of MAO, MAO-B has been believed to be involved in dopamine degradation, which supports the idea that the therapeutic efficacy of MAO-B inhibitors in Parkinson’s disease can be attributed to an increase in extracellular dopamine concentration. However, this belief has been controversial. Here, by utilizing in vivo phasic and basal electrochemical monitoring of extracellular dopamine with fast-scan cyclic voltammetry and multiple-cyclic square wave voltammetry and ex vivo fluorescence imaging of dopamine with GRABDA2m, we demonstrate that MAO-A, but not MAO-B, mainly contributes to striatal dopamine degradation. In contrast, our whole-cell patch-clamp results demonstrated that MAO-B, but not MAO-A, was responsible for astrocytic GABA-mediated tonic inhibitory currents in the rat striatum. We conclude that, in contrast to the traditional belief, MAO-A and MAO-B have profoundly different roles: MAO-A regulates dopamine levels, whereas MAO-B controls tonic GABA levels.

Highlights

Monoamine oxidase (MAO) is an enzyme that catalyzes the oxidative deamination of biogenic amines[1,2]
KDS2010 treatment (10 mg kg−1; MAO-B inhibitor) did not alter the peak DA current (91.37 ± 7.28%) (Fig. 1e, f, g). Another MAO-B inhibitor, selegiline, showed a similar effect to KDS2010 (Supplementary Fig. 1a-c). These findings suggest that MAO-A, but not MAO-B, could be responsible for the degradation of intracellular DA, which is directly associated with the amount of DA released upon electrical stimulation
In vivo electrochemical monitoring of DA currents using fast-scan cyclic voltammetry (FSCV) and multiple-cyclic square wave voltammetry (M-CSWV) and ex vivo DA imaging using a GRABDA2m sensor revealed that the acute pharmacological inhibition of MAO-B by KDS2010 and selegiline did not affect either phasic or basal DA levels, which was inconsistent with the traditional belief

Summary

Introduction

Monoamine oxidase (MAO) is an enzyme that catalyzes the oxidative deamination of biogenic amines[1,2]. MAOs are localized in the outer membrane of mitochondria and have an important role in the metabolism of neuroactive monoamines, such as dopamine (DA), norepinephrine, serotonin, and melatonin, in the brain[3]. The two isozymes have differential cellular localizations in the brain: MAO-A is predominantly localized at the nigrostriatal DAergic axon terminals, while MAOB is mostly localized in astrocytes and serotonergic neurons[6,7,8]. Owing to their substrate specificities, selective MAO inhibitors have been designed to inhibit the activity of a specific type of isoenzyme: clorgiline and moclobemide inhibit MAO-A, while selegiline, rasagiline, safinamide, and KDS2010 inhibit MAO-B9–12. Most of these MAO-A and MAO-B inhibitors are differentially prescribed to patients with depression and Parkinson’s disease (PD), respectively[9]

Methods

Results

Conclusion