NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2 Receptor Stimulation: Involvement in Behavioral Repetition
NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2 Receptor Stimulation: Involvement in Behavioral Repetition
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DOI：
10.1523/jneurosci.2121-20.2021
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发表时间：
2021-03-24
影响因子：
5.3
通讯作者：
Yabe-Nishimura, Chihiro
中科院分区：
文献类型：
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作者：
Asaoka, Nozomi;Ibi, Masakazu;Yabe-Nishimura, Chihiro
重复行为是一种被广泛观察到的神经精神症状。纹状体中异常的多巴胺能信号是与行为重复相关的因素之一；然而，诱导重复行为的分子机制尚不清楚。在这里，我们证明了超氧化物产生酶NADPH氧化酶的NOX1亚型通过促进中央纹状体(CS)的兴奋性突触输入来调节小鼠的重复行为。在雄性C57BL/6J小鼠中，重复刺激D-2受体可引起异常行为重复和持久化行为。NOX1缺乏或急性药物抑制NOX1可显著缩短重复的D-2受体刺激引起的重复行为，而不影响对单个D-2受体刺激的运动反应。在脑区中，Nox1在纹状体有丰富的表达，重复刺激多巴胺D-2受体进一步增加了CS中Nox1的表达水平，但在背侧纹状体不表达。电生理分析表明，重复刺激D-2受体促进了CS间接通路中间棘神经元(IMSN)的兴奋性输入，这种作用可被NOX1的基因缺失或药物抑制所抑制。Nox1缺乏增强了蛋白酪氨酸磷酸酶的活性，并减弱了CS iMSN突触增强所需的激活的Src激酶的积聚。在CS中抑制NOX1或β-arrestin足以改善重复行为。纹状体特异的Nox1基因敲除也改善了重复和持之以恒的行为。综上所述，这些结果表明，NOX1在CS iMSN中作为突触易化的增强子，在异常的多巴胺信号与行为重复和坚持之间的分子联系中发挥关键作用。
Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D-2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D-2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D-2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D-2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. Electrophysiological analyses revealed that repeated D-2 receptor stimulation facilitated excitatory inputs in the CS indirect pathway medium spiny neurons (iMSNs), and this effect was suppressed by the genetic deletion or pharmacological inhibition of NOX1. Nox1 deficiency potentiated protein tyrosine phosphatase activity and attenuated the accumulation of activated Src kinase, which is required for the synaptic potentiation in CS iMSNs. Inhibition of NOX1 or beta-arrestin in the CS was sufficient to ameliorate repetitive behavior. Striatal-specific Nox1 knockdown also ameliorated repetitive and perseverative behavior. Collectively, these results indicate that NOX1 acts as an enhancer of synaptic facilitation in CS iMSNs and plays a key role in the molecular link between abnormal dopamine signaling and behavioral repetition and perseveration.