NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex
NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex
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DOI：
10.1073/pnas.0308455101
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发表时间：
2004-06-01
影响因子：
11.1
通讯作者：
Moghaddam, B
中科院分区：
文献类型：
--
作者：
Jackson, ME;Homayoun, H;Moghaddam, B
与额叶功能障碍相关的认知缺陷是精神分裂症患者长期残疾的决定因素，现有药物无法有效治疗。临床研究表明，在接受n -甲基- d -天冬氨酸（NMDA）拮抗剂治疗的健康个体中，这些缺陷的许多方面都是短暂诱导的。这些发现和最近的遗传联系研究强烈地暗示了精神分裂症中NMDA受体缺乏，并表明逆转这种缺乏与治疗精神分裂症的认知症状有关。尽管关于NMDA拮抗剂治疗在人类和实验动物中的作用的行为数据丰富，但对于NMDA缺乏的一般状态影响皮质神经元功能的机制仍缺乏基本的了解。通过对自由运动大鼠的整体记录，我们发现NMDA拮抗剂治疗，在损害工作记忆的剂量下，增强了大多数前额皮质神经元的放电率。这种增强与行为刻板印象的表达相关，是由不规则释放的单峰数量增加引起的。在尖峰活动增加的同时，有组织的爆发活动显著减少。这些结果确定了NMDA受体缺乏可能破坏额叶功能的两种不同机制：紊乱的尖峰活动增加，这可能增强皮层噪音和虚假信息的传递；以及突发活动的减少，这降低了皮层神经元的传递效率。这些发现为精神分裂症的NMDA受体缺乏模型提供了生理基础，并可能阐明这种疾病中皮质功能障碍的本质。
Cognitive deficits associated with frontal lobe dysfunction are a determinant of long-term disability in schizophrenia and are not effectively treated with available medications. Clinical studies show that many aspects of these deficits are transiently induced in healthy individuals treated with N-methyl-D-aspartate (NMDA) antagonists. These findings and recent genetic linkage studies strongly implicate NMDA receptor deficiency in schizophrenia and suggest that reversing this deficiency is pertinent to treating the cognitive symptoms of schizophrenia. Despite the wealth of behavioral data on the effects of NMDA antagonist treatment in humans and laboratory animals, there is a fundamental lack of understanding about the mechanisms by which a general state of NMDA deficiency influences the function of cortical neurons. Using ensemble recording in freely moving rats, we found that NMDA antagonist treatment, at doses that impaired working memory, potentiated the firing rate of most prefrontal cortex neurons. This potentiation, which correlated with expression of behavioral stereotypy, resulted from an increased number of irregularly discharged single spikes. Concurrent with the increase in spike activity, there was a significant reduction in organized bursting activity. These results identify two distinct mechanisms by which NMDA receptor deficiency may disrupt frontal lobe function: an increase in disorganized spike activity, which may enhance cortical noise and transmission of disinformation; and a decrease in burst activity, which reduces transmission efficacy of cortical neurons. These findings provide a physiological basis for the NMDA receptor deficiency model of schizophrenia and may clarify the nature of cortical dysfunction in this disease.