Post-pubertal Difference in Nigral Dopaminergic Cells Firing in the Schizophrenia Model Prepared by Perinatal Challenges of a Cytokine, EGF
Post-pubertal Difference in Nigral Dopaminergic Cells Firing in the Schizophrenia Model Prepared by Perinatal Challenges of a Cytokine, EGF
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DOI：
10.1016/j.neuroscience.2020.06.003
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发表时间：
2020-08-10
期刊：
影响因子：
3.3
通讯作者：
Nawa, Hiroyuki
中科院分区：
文献类型：
--
作者：
Namba, Hisaaki;Nawa, Hiroyuki
人类精神分裂症通常在青春期期间和之后发展；然而，这一发病时间窗口的特异性的生物学基础仍有待确定。在目前的研究中，我们使用我们自己的精神分裂症动物模型来研究这一知识差距。啮齿动物和猴子受到一种名为表皮生长因子(EGF)的细胞因子的挑战，因为已知新生儿在青春期后阶段会表现出各种行为和认知异常。我们使用EGF挑战的小鼠作为精神分裂症的动物模型，以评估该模型在青春期前后对黑质多巴胺神经元的电生理影响。在体单单位记录显示，EGF模型小鼠青春期后黑质致密部多巴胺神经元的突发性放电显著高于对照组，而青春期前未观察到这种差异。突发性放电的增加伴随着影响多巴胺神经元放电模式的钙激活K+(I-SK)电流的下降。在体内，在黑质局部应用SK通道阻滞剂阿帕明(80mU M)，对EGF模型小鼠的爆发式放电增加的作用不如对照组，提示ISK在该模型中的病理作用。因此，这些结果表明，青春期后中脑多巴胺能神经元的异常过度活动与该模型行为缺陷的时间特异性有关，并支持这种多巴胺能异常可能与青春期精神分裂症的发病有关的假说。(C)2020 IBRO。爱思唯尔有限公司出版。保留所有权利。
Schizophrenia in humans typically develops during and after adolescence; however, the biological underpinning for the specificity of this onset time window remains to be determined. In the present study, we investigated this knowledge gap using our own animal model for schizophrenia. Rodents and monkeys challenged with a cytokine, epidermal growth factor (EGF), as neonates are known to exhibit various behavioral and cognitive abnormalities at the post-pubertal stage. We used the EGF-challenged mice as an animal model for schizophrenia to evaluate the electrophysiological impact of this modeling on nigral dopamine neurons before and after puberty. In vivo single unit recording revealed that the burst firing of putative dopamine neurons in substantia nigra pars compacta was significantly higher in the post-pubertal stage of the EGF model than in that of control mice; in contrast, this difference was not observed in the pre-pubertal stage. The increase in burst firing was accompanied by a decline in Ca2+-activated K+ (I-SK) currents, which influence the firing pattern of dopamine neurons. In vivo local application of the SK channel blocker apamin (80 mu M) to the substantia nigra was less effective at increasing burst firing in the EGF model than in control mice, suggesting the pathologic role of the ISK decrease in this model. Thus, these results suggest that the aberrant post-pubertal hyperactivity of midbrain dopaminergic neurons is associated with the temporal specificity of the behavioral deficit of this model, and support the hypothesis that this dopaminergic aberration could be implicated in the adolescent onset of schizophrenia. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.