Division of Experimental Therapeutics, Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute, Orangeburg, NY, USA.
Neuropsychopharmacology. 2018 Feb;43(3):571-582. doi: 10.1038/npp.2017.176. Epub 2017 Aug 17.
Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (θ)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and θ-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (α) and beta (β) frequency ranges. PCP treatment also significantly reduced α-frequency response to standard stimuli while increasing θ-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to θ-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.
听觉失匹配负波（MMN）产生缺陷是精神分裂症中最广泛复制的神经生理异常之一，与 N-甲基-D-天冬氨酸受体（NMDAR）介导的神经传递功能障碍有关。在这里，我们评估了啮齿动物 MMN 的生理特性，以及对 NMDAR 激动剂和拮抗剂治疗的敏感性，与精神分裂症已知的功能障碍模式相对应。在使用盐水、苯环利定（PCP，15mg/kg/d 通过渗透微型泵）或 PCP+甘氨酸（16%重量饮食）干预治疗的大鼠中，在基线和治疗 2 周和 4 周后，获得了对频率和持续时间偏差的硬膜外神经生理反应，以及对标准刺激的反应。使用事件相关电位（ERP）和神经振荡（诱发功率）方法分析了反应。在基线时，啮齿动物持续时间 MMN 与增加的θ（θ）频率反应有关，类似于在人类中观察到的反应。PCP 显著降低了啮齿动物持续时间 MMN（p<0.001）和θ带（p<0.01）反应。同时给予甘氨酸治疗可预防 PCP 的作用（p<0.01 与 PCP 单独治疗相比）。与刺激特异性适应（SSA）相关的效应主要发生在α（α）和β（β）频率范围内。PCP 治疗还显著降低了标准刺激的α-频率反应，同时增加了θ 带反应，再现了在精神分裂症中观察到的缺陷模式。总的来说，我们证明了啮齿动物持续时间 MMN 表现出与人类 MMN 相似的神经振荡特征，并且对 NMDAR 拮抗剂和激动剂的给药敏感。这些发现加强了最近将 MMN 缺陷与θ 带神经振荡功能障碍联系起来的人类研究，并支持使用啮齿动物持续时间 MMN 作为一种转化生物标志物，用于研究精神分裂症中局部回路功能受损的机制。
