2026 ECNP Congress

PS02-2087

Elevated monoamine oxidase A in the prelimbic cortex: role in neurotransmission and emotional behaviour

Phuoc Quy Long Nguyen — R. Lebeau, R. Zhou, T. Tomoda, J.H. Meyer, E. Sibille, J.P. Guilloux · Universite Paris-Saclay, INSERM- CESP MOODS Team, Orsay, France

2026 ECNP Congress

Current pharmacotherapies treating major depressive disorder (MDD) primarily act as monoamine reuptake inhibitors, increasing serotonergic (5-HT) and/or noradrenergic (NE) neurotransmission, however, with limited efficacy in a substantial proportion of patients [1]. Elevated monoamine oxidase type A (MAO-A), an enzyme mainly degrading 5-HT and NE, is a pathological feature of MDD and stress-related states [2–4], supporting the hypothesis that increased MAO-A activity contributes to MDD vulnerability and reduced antidepressant response. Our study aimed to test whether increased MAO-A expression in the medial prefrontal cortex (mPFC) causally alters monoamine levels, emotional behavior and antidepressant response. We developed a humanized mouse model using a viral vector to introduce a human ortholog of MAO-A (hMAO-A) specifically in the mPFC pyramidal neurons or astrocytes in mice as MAO-A is abundantly expressed in both cell types in the mPFC [5]. Immunofluorescence analysis confirmed 40~50% of cells infected per injected area with an average of ~2.7-fold increase in MAOA protein expression per infected cell, resulting in a ~60% net increase in MAOA levels over the control. Three weeks after injection, behavioral emotionality was tested in the open field, the elevated plus maze, the novelty-suppressed feeding and the splash test. Microdialysis was performed in the mPFC to assess basal extracellular 5-HT levels ([5-HT]ext) and the effects of acute fluoxetine (18 mg/kg, i.p.) and ketamine (10 mg/kg, i.p.) administration. Finally, effects of chronic fluoxetine (18 mg/kg/day) administration on emotionality were tested. Statistical analyses included t-tests, Mann–Whitney U tests, one-way, two-way ANOVA with post hoc comparisons, and Kaplan–Meier log-rank tests, selected based on data distribution. Microdialysis in neuronal high hMAO-A mice revealed a significant 57% decrease in basal [5-HT]ext in the mPFC compared to GFP controls (p<0.01). Acute fluoxetine administration significantly increased [5-HT]ext in mPFC in control mice (p<0.01), but failed to increase [5-HT]ext in elevated hMAO-A mice (with neuronal expression: p=0.20; astrocytic expression: p>0.99). Acute ketamine did not alter [5-HT]ext in the mPFC in either GFP or hMAO-A mice, consistent with its antidepressant mechanism being independent of serotonergic neurotransmission. Elevated hMAO-A in pyramidal neurons did not alter anxiety-like behavior but induced anhedonia-like behavior, as evidenced by a 31% decrease in grooming duration compared to GFP-control mice (p<0.05) in the splash test. In contrast, elevated hMAO-A in astrocytes increased anxiety-like behavior, with a significant increase in latency to feed of the novelty-suppressed feeding test compared to controls (log-rank test, p<0.05), but did not affect anhedonia. Surprisingly, chronic fluoxetine administration induced an anxiogenic effect in the open field (p<0.01) and in the novelty-suppressed feeding (p<0.05) in astrocytic high hMAO-A mice. Overall, these results demonstrate that elevated MAO-A activity in the mPFC alters emotional behavior in a cell type-specific manner, producing either anxiety-like or anhedonia-like phenotypes, which cannot be rescued by chronic fluoxetine. Increased MAO-A also reduces [5-HT]ext at baseline and alters fluoxetine response. These findings identify cell-type-specific MAO-A overactivity in the mPFC as a contributor to emotional dysregulation and antidepressant treatment resistance, offering a mechanistic basis for novel therapeutic strategies.

References

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