Perinatal Epidermal Growth Factor Signal Perturbation Results in the Series of Abnormal Auditory Oscillations and Responses Relevant to Schizophrenia
Perinatal Epidermal Growth Factor Signal Perturbation Results in the Series of Abnormal Auditory Oscillations and Responses Relevant to Schizophrenia
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DOI：
10.1093/schizbullopen/sgaa070
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hiroyoshi Inaba;Ryota Kai;H. Namba;H. Sotoyama;E. Jodo;F. Nin;H. Hibino;H. Yabe;S. Eifuku;A. Horii;H. Nawa
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文献类型：
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作者：
Hiroyoshi Inaba;Ryota Kai;H. Namba;H. Sotoyama;E. Jodo;F. Nin;H. Hibino;H. Yabe;S. Eifuku;A. Horii;H. Nawa
听觉神经生理反应，如稳态反应，事件相关电位P300/P3，和相位振幅耦合，是精神分裂症的有前途的翻译生物标志物，但其分子基础知之甚少。专注于ErbB受体信号，涉及精神分裂症和听觉处理/认知，我们探讨了ErbB信号和这些听觉特征之间的因果生物学联系与大鼠的实验干预。我们周边挑战大鼠幼鼠与羊膜ErbB配体，表皮生长因子（EGF），其特点是一系列的这些听觉皮层电图的措施。听觉脑干反应（ABR）和皮质ON反应也在麻醉下进行了评估，以估计更高的大脑区域的影响。听觉稳态范式显示衰减的频谱功率和相位同步40 Hz的刺激EGF挑战的大鼠。我们观察到持续时间不匹配负性样电位的减少和P3 a反应的延迟，所有这些都与精神分裂症患者的听觉病理生理特征有关。此外，围产期EGF挑战导致听觉皮层内的θ-α/β和θ-γ耦合增强以及ABR的变化。然而，EGF挑战保留了皮质ON反应的正常范围，可能排除了他们的基本听觉缺陷。围产期暴露的ErbB配体大鼠惊人地再现了整个系列的异常听觉反应和振荡先前报道的精神分裂症患者。因此，这些研究结果表明，ErbB/EGF信号的发育缺陷可能参与与精神分裂症相关的听觉病理生理。
Auditory neurophysiological responses, such as steady-state responses, event-related potential P300/P3, and phase-amplitude coupling, are promising translational biomarkers for schizophrenia, but their molecular underpinning is poorly understood. Focusing on ErbB receptor signals that are implicated in both schizophrenia and auditory processing/cognition, we explored the causal biological links between ErbB signals and these auditory traits with an experimental intervention into rats. We peripherally challenged rat pups with one of the amniotic ErbB ligands, epidermal growth factor (EGF), and characterized its consequence on the series of these auditory electrocorticographic measures. Auditory brainstem responses (ABRs) and cortical ON responses were also assessed under anesthesia to estimate the influence of higher brain regions. An auditory steady-state paradigm revealed attenuation of spectral power and phase synchrony to 40-Hz stimuli in EGF-challenged rats. We observed a reduction in duration mismatch negativity-like potentials and a delay of P3a responses, all of which are relevant to the reported auditory pathophysiological traits of patients with schizophrenia. Moreover, the perinatal EGF challenges resulted in enhanced theta-alpha/beta and theta-gamma coupling within the auditory cortex and changes in ABRs. However, the EGF challenges retained the normal ranges of cortical ON responses, potentially ruling out their fundamental auditory deficits. Perinatal exposure of an ErbB ligand to rats strikingly reproduced the whole series of aberrant auditory responses and oscillations previously reported in patients with schizophrenia. Accordingly, these findings suggest that developmental deficits in ErbB/EGF signaling might be involved in the auditory pathophysiology associated with schizophrenia.