MAO-A increased activity : role in REsponse to antidepressant & Emotionality – MAO-REE

Major depressive disorders (MDD) are the most frequent mental illnesses. Most antidepressants (ADs) increase monoamines but have restricted efficacies (~50%), which can lead to treatment resistant depression (TRD). A potential mechanism underlying both MDD and the effects of ADs is increased levels of the monoamine oxidase A (MAOA) that metabolizes monoamines. Elevated MAOA is found across the brain in MDD, correlates with symptom severity, and may hampers monoaminergic ADs efficacy. We propose to test this MAOA-MDD causal link by developing a humanized mouse model overexpressing the human MAOA (hMAOA) as a model of MDD and TRD pathology. Mice will be injected with an AAV viral vector allowing the selective and specific overexpression of hMAOA in brain regions associated with mood regulation (prefrontal cortex or ventral hippocampus). Since MAOA is expressed by both neuronal (monoaminergic and non-monoaminergic) and glial cells, cell-specific AAVs will be used to increase hMAOA selectively in monoaminergic, glutamatergic neurons and astrocytes. 1) Behavioural and neurochemical changes related to increased hMAOA levels will be tested in basal conditions and after chronic stress exposure. 2) The effects of increased hMAOA on monoaminergic and non-monoaminergic ADs used for alleviating MDD and TRD will be tested. 3) Elevated hMAOA may cause oxidative stress and associated molecular cascade of events suggesting additional MAOA-related and non-monoaminergic dependent factors of vulnerability or resistance to AD. Thus, effects of MAOA overexpression on markers of oxidative stress and mitochondrial activity will be tested. Finally transcriptomic changes induced by hMAO elevation will be monitored using RNASeq. Overall, our project will aim at understanding the contribution of elevated MAOA to MDD-TRD vulnerability and treatment response, and at identifying molecular changes associated with increased MAOA activity.