RHYTHMIC THETA AND DELTA ACTIVITY OF CORTICAL AND HIPPOCAMPAL NEURONAL NETWORKS IN GENETICALLY OR PHARMACOLOGICALLY INDUCED N-METHYL-D-ASPARTATE RECEPTOR HYPOFUNCTION UNDER URETHANE ANESTHESIA
RHYTHMIC THETA AND DELTA ACTIVITY OF CORTICAL AND HIPPOCAMPAL NEURONAL NETWORKS IN GENETICALLY OR PHARMACOLOGICALLY INDUCED N-METHYL-D-ASPARTATE RECEPTOR HYPOFUNCTION UNDER URETHANE ANESTHESIA
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DOI：
10.1016/j.neuroscience.2013.01.058
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发表时间：
2013-05-01
期刊：
影响因子：
3.3
通讯作者：
Hajos, M.
中科院分区：
文献类型：
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作者：
Kiss, T.;Feng, J.;Hajos, M.
N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂在健康受试者中模拟精神分裂症的几种症状，并用于临床前疾病模型。在本研究中，我们评估了药物和遗传因素导致的NMDAR功能低下对大鼠和小鼠，包括NMDAR亚型(Grin1)小鼠神经网络振荡的影响。在麻醉状态下，记录了大鼠腹内侧前额叶皮质(MPFC)和海马区(CA1)的场电位，以及Grin1和野生型(WT)小鼠对脑干刺激的自发和诱发的海马theta振荡。Alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic酸受体阳性变构调节剂LY451395在GRIN1小鼠和WT小鼠中测试了MK-801攻击后的效果。大鼠mPFC和CA1的记录分别显示了规则的Delta和theta振荡，这两种振荡分别被MK-801干扰。在WT小鼠中，MK-801降低了自发和诱发的海马theta能力。年龄匹配的Grin1小鼠表现出异常的海马场电位，与WT小鼠注射MK-801后的活动相似，但也有癫痫样放电。服用MK-801的大鼠和小鼠的NMDAR占有率都很高(84-98%)，这与Grin1小鼠NMDAR表达减少约90%-95%相当。LY451395可显著改善经MK-801或Grin1诱导的WT小鼠的CA1-theta振荡。这些发现表明，在急性药物或遗传操作导致NMDAR功能下降后，网络活动发生了类似的变化，尽管不是相同的，这表明这些新的神经生理学模型可以用于评估针对谷氨酸神经传递的候选药物。(C)2013年IBRO。爱思唯尔有限公司出版。保留所有权利。
N-Methyl-D-aspartate receptor (NMDAR) antagonists mimic several symptoms of schizophrenia in healthy subjects, and are used in preclinical disease models. In the present study, the impact of pharmacologically and genetically induced NMDAR hypofunction was assessed in rats and mice, including the NMDAR hypomorphic (Grin1) mice, with respect to neuronal network oscillations. Field potentials were recorded from the ventro-medial prefrontal cortex (mPFC) and hippocampus (CA1) in rats, as well as spontaneous and elicited hippocampal theta oscillations in response to brainstem stimulation in Grin1 and wild-type (WT) mice under anesthesia. Effects of the alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor positive allosteric modulator LY451395 were tested in Grin1 mice and in WT mice following an MK-801 challenge. Recordings from the mPFC and CA1 in rats revealed regular delta and theta oscillations, respectively, which were disrupted by MK-801. In WT mice, MK-801 reduced both spontaneous and elicited hippocampal theta power. Age-matched Grin1 mice showed abnormal hippocampal field potentials, resembling activity seen after administration of MK-801 in WT mice, but also epileptiform discharges. Administration of MK-801 achieved high levels of NMDAR occupancy (84-98%) in both rats and mice, which is comparable to the approximately 90-95% reduction of NMDAR expression in the Grin1 mouse. Impaired elicited CA1 theta oscillation in WT mice following MK-801, or Grin1 mice was significantly improved by LY451395. These findings demonstrate similar, although not identical, changes in network activity following reduction in functioning NMDARs induced by acute pharmacological or genetic manipulations, indicating that these novel neurophysiological models could be used in evaluating drug candidates targeting glutamate neurotransmission. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.