Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice
Ketamine independently modulated power and phase-coupling of theta oscillations in Sp4 hypomorphic mice
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DOI：
10.1371/journal.pone.0193446
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发表时间：
2018-03-07
期刊：
影响因子：
3.7
通讯作者：
Sejnowski, Terrence J.
中科院分区：
文献类型：
--
作者：
Wang, Xin;Pinto-Duarte, Antonio;Sejnowski, Terrence J.
Sp 4是人类SP 4的鼠同源物，是多种精神疾病的风险基因，其表达减少导致小鼠N-甲基-D-天冬氨酸（NMDA）功能减退，产生精神分裂症的行为表型，包括对氯胺酮的超敏反应。随着越来越多的分子机制和行为表型的证据建立Sp 4亚型作为一个有前途的动物模型，Sp 4亚型的系统水平的神经回路机制，特别是网络动力学的认知功能，仍然知之甚少。我们试图在本研究中，通过记录清醒行为野生型和Sp 4亚纯型小鼠的多通道硬膜外脑电图（EEG）来缩小这一知识差距。我们的特点是皮层θ波段功率和相位耦合表型，一个已知的神经回路基板的认知功能，并进一步研究了亚麻醉剂量的氯胺酮对θ异常独特的Sp 4亚形态的影响。SP 4 hypomorphic小鼠有显着升高的theta功率局部额叶和顶叶，一个更明显的theta相位进展沿着的神经轴，和一个更强的额叶-顶叶theta耦合。急性亚麻醉氯胺酮不影响野生型动物的θ功率，但显着降低了SP 4亚纯型小鼠，几乎完全中和他们过多的额叶/顶叶θ功率。氯胺酮并没有显着改变皮质θ相位进展无论是野生型或SP 4亚纯动物，但显着加强皮质θ相位耦合野生型，但不是在SP 4亚纯动物。我们的研究结果表明，皮质θ振荡独特的Sp 4亚纯型小鼠密切模仿精神分裂症的内表型的休息状态表型。此外，氯胺酮独立调制Sp 4亚形态异常的θ功率和相位耦合，这表明单独的潜在神经回路机制。
Reduced expression of Sp4, the murine homolog of human SP4, a risk gene of multiple psychiatric disorders, led to N-methyl-D-aspartate ( NMDA) hypofunction in mice, producing behavioral phenotypes reminiscent of schizophrenia, including hypersensitivity to ketamine. As accumulating evidence on molecular mechanisms and behavioral phenotypes established Sp4 hypomorphism as a promising animal model, systems-level neural circuit mechanisms of Sp4 hypomorphism, especially network dynamics underlying cognitive functions, remain poorly understood. We attempted to close this gap in knowledge in the present study by recording multi-channel epidural electroencephalogram ( EEG) from awake behaving wildtype and Sp4 hypomorphic mice. We characterized cortical theta-band power and phase-coupling phenotypes, a known neural circuit substrate underlying cognitive functions, and further studied the effects of a subanesthetic dosage of ketamine on theta abnormalities unique to Sp4 hypomorphism. Sp4 hypomorphic mice had markedly elevated theta power localized frontally and parietally, a more pronounced theta phase progression along the neuraxis, and a stronger frontal-parietal theta coupling. Acute subanesthetic ketamine did not affect theta power in wildtype animals but significantly reduced it in Sp4 hypomorphic mice, nearly completely neutralizing their excessive frontal/parietal theta power. Ketamine did not significantly alter cortical theta phase progression in either wildtype or Sp4 hypomorphic animals, but significantly strengthened cortical theta phase-coupling in wildtype, but not in Sp4 hypomorphic animals. Our results suggested that the resting-state phenotypes of cortical theta oscillations unique to Sp4 hypomorphic mice closely mimicked a schizophrenic endophenotype. Further, ketamine independently modulated Sp4 hypomorphic anomalies in theta power and phase-coupling, suggesting separate underlying neural circuit mechanisms.