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

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 GRAB(DA2m), 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. Parkinson's disease: rewriting the roles of a critical enzyme The inhibition of two forms of an enzyme that modulate key processes in the brain has different benefits for patients with Parkinson's disease than previously thought. Monoamine oxidase (MAO) is present in the brain as MAO-A and MAO-B, both of which were thought to be involved in dopamine degradation. MAO inhibitors are used to limit dopamine degradation in Parkinson's disease and depression, improving symptoms by increasing levels of usable dopamine. In experiments on rats, Hyun-U Cho at Hanyang University, Seoul, South Korea, and coworkers have shown that MAO-A, but not MAO-B, affects dopamine degradation. The team found that MAO-B instead mediates the synthesis of a key neurotransmitter, GABA, the upregulation of which is linked to Parkinson's motor symptoms. Taking MAO-B inhibitors may be addressing these symptoms, explaining why patients show improvement.