NMDARs mediate the role of monoamine oxidase A in pathological aggression.
NMDARs mediate the role of monoamine oxidase A in pathological aggression.
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DOI：
10.1523/jneurosci.0225-12.2012
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发表时间：
2012-06-20
期刊：
影响因子：
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通讯作者：
Shih JC
中科院分区：
文献类型：
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作者：
Bortolato M;Godar SC;Melis M;Soggiu A;Roncada P;Casu A;Flore G;Chen K;Frau R;Urbani A;Castelli MP;Devoto P;Shih JC
越来越多的证据表明，单胺氧化酶A（MAO A），催化5-羟色胺（5-HT）和去甲肾上腺素（NE）降解的关键酶，是反社会和攻击行为的病理生理学的主要因素。因此，雄性MAO A缺陷的人类和小鼠表现出对应激反应的攻击性爆发的极端倾向。由于NMDAR调节对社会和环境刺激的情绪反应，我们假设它们参与了由MAO A介导的攻击性调节。与WT雄性小鼠相比，MAO A KO对应物在所有脑区域中表现出5-HT和NE水平的增加，但谷氨酸浓度和NMDAR结合没有差异。值得注意的是，MA 0 A KO小鼠的前额叶皮质（PFC）表现出NR 2A和NR 2B的较高表达，以及较低水平的糖基化NR 1亚基。与这些变化一致，PFC中NMDAR的电流幅度和衰减时间显著降低。此外，这些受体的电流对NMDAR复合物（地佐环平）以及NR 2A（PEAQX）和NR 2B（Ro 25-6981）亚基的拮抗剂的作用超敏感。值得注意的是，这些药剂的全身给药以不固有地影响运动活动的剂量选择性地对抗MA 0 A KO小鼠中增强的攻击性。我们的研究结果表明，单胺氧化酶A在病理性攻击的作用可能是介导的NMDAR亚基组成的PFC的变化，并指出这个受体的反社会人格的分子基础的关键功能。
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.