NMDARs mediate the role of monoamine oxidase A in pathological aggression.
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.
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA.
Marco
M
Bortolato
Sean C
SC
Godar
Miriam
M
Melis
Alessio
A
Soggiu
Paola
P
Roncada
Angelo
A
Casu
Giovanna
G
Flore
Kevin
K
Chen
Roberto
R
Frau
Andrea
A
Urbani
M Paola
MP
Castelli
Paola
P
Devoto
Jean C
JC
Shih
D000374:Aggression / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000987:Antisocial Personality Disorder / Q000503:physiopathology*; D001345:Autoradiography; D001665:Binding Sites; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D055724:Electrophysiological Phenomena; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics / Q000502:physiology*; D009043:Motor Activity / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D016548:Prosencephalon / Q000201:enzymology; D011810:Quinoxalines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism
C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; D010636:Phenols; D010880:Piperidines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D012701:Serotonin; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D008995:Monoamine Oxidase; D009638:Norepinephrine