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首页> 外文期刊>The European Journal of Neuroscience >Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling
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Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling

机译：持续的N-甲基-d-天冬氨酸受体功能低下会重塑多巴胺系统并损害相位信号

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Chronic N-methyl-d-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e. tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D2 autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing.
机译：慢性N-甲基-d-天冬氨酸受体（NMDAR）功能低下已被提议为精神分裂症症状的一个促成因素。但是，尚不清楚整个发育过程中持续的NMDAR功能低下如何影响与该疾病有关的其他神经递质系统。检查了多巴胺神经元的生物化学和活性，以确定持续的NMDAR功能低下是否引起高多巴胺痛状态。我们报告说，NMDARs的全球性遗传减少导致多巴胺神经元的重塑，从而严重影响了多巴胺稳态的两个关键调节因子，即酪氨酸羟化酶和多巴胺转运蛋白。在NR1基因敲除小鼠中，多巴胺的合成和释放减弱，多巴胺清除率增加。尽管这些变化将具有减少多巴胺传递的作用，但我们证明了这些小鼠中存在一种高多巴胺痛状态，因为多巴胺D2自身受体被脱敏。支持该结论的是，NR1敲低的多巴胺神经元具有较高的滋补生速。尽管进补射击的频率较高，但相位信号却受到损害，而使用模拟相位射击的外源高频刺激无法实现多巴胺溢出。通过检查多巴胺神经传递的几个参数，我们提供证据表明慢性NMDAR功能低下导致突触多巴胺升高。减轻高多巴胺痛的补偿机制也影响通过相放电产生多巴胺激增的能力。

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