RT Journal Article
SR Electronic
T1 NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 8574
OP 8582
DO 10.1523/JNEUROSCI.0225-12.2012
VO 32
IS 25
A1 Bortolato, Marco
A1 Godar, Sean C.
A1 Melis, Miriam
A1 Soggiu, Alessio
A1 Roncada, Paola
A1 Casu, Angelo
A1 Flore, Giovanna
A1 Chen, Kevin
A1 Frau, Roberto
A1 Urbani, Andrea
A1 Castelli, M. Paola
A1 Devoto, Paola
A1 Shih, Jean C.
YR 2012
UL http://www.jneurosci.org/content/32/25/8574.abstract
AB 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.