NMDARs mediate the role of monoamine oxidase A in pathological aggression

• Published in: The Journal of neuroscience Vol. 32; no. 25; pp. 8574 - 8582
• Main Authors: Bortolato, Marco, Godar, Sean C, Melis, Miriam, Soggiu, Alessio, Roncada, Paola, Casu, Angelo, Flore, Giovanna, Chen, Kevin, Frau, Roberto, Urbani, Andrea, Castelli, M Paola, Devoto, Paola, Shih, Jean C
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 20.06.2012
• Subjects: Aggression - drug effects; Aggression - physiology; Animals; Antisocial Personality Disorder - physiopathology; Autoradiography; Binding Sites; Blotting, Western; Corpus Striatum - metabolism; Dizocilpine Maleate - pharmacology; Electrophysiological Phenomena; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - metabolism; Hippocampus - metabolism; Male; Mice; Mice, Knockout; Monoamine Oxidase - genetics; Monoamine Oxidase - physiology; Motor Activity - physiology; Norepinephrine - metabolism; Patch-Clamp Techniques; Phenols - pharmacology; Piperidines - pharmacology; Prosencephalon - enzymology; Quinoxalines - pharmacology; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - physiology; Serotonin - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.0225-12.2012

Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality.