Electroencephalography Biomarkers of α5-GABA Positive Allosteric Modulators in Rodents

IF 3.7 Q2 NEUROSCIENCES Biological psychiatry global open science Pub Date : 2025-03-01 Epub Date: 2024-12-19 DOI:10.1016/j.bpsgos.2024.100435

Frank Mazza , Alexandre Guet-McCreight , Thomas D. Prevot , Taufik Valiante , Etienne Sibille , Etay Hay

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Abstract

Background

Reduced cortical inhibition mediated by GABA (gamma-aminobutyric acid) is reported in depression, anxiety disorders, and aging. A novel positive allosteric modulator that specifically targets the α5-GABA_A receptor subunit (α5-PAM), ligand GL-II-73 shows anxiolytic, antidepressant, and procognitive effects without the common side effects associated with nonspecific modulation by benzodiazepines such as diazepam, thus suggesting novel therapeutic potential. However, it is unknown whether α5-PAM has detectable signatures in clinically relevant brain electroencephalography (EEG).

Methods

We analyzed EEG in 10 freely moving rats at baseline and following injections of α5-PAM (GL-II-73) and diazepam.

Results

We showed that α5-PAM specifically decreased theta peak power, whereas diazepam shifted peak power from high to low theta while increasing beta and gamma power. EEG decomposition showed that these effects were periodic and corresponded to changes in theta oscillation event duration.

Conclusions

Thus, our study shows that α5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable noninvasive monitoring of α5-PAM treatment efficacy.

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啮齿动物α5-GABA阳性变构调节剂的脑电图生物标志物

研究背景：GABA （γ -氨基丁酸）介导的皮质抑制减少在抑郁症、焦虑症和衰老中有报道。一种新的正变构调节剂，特异性靶向α5-GABAA受体亚基（α5-PAM），配体GL-II-73具有抗焦虑、抗抑郁和促进认知的作用，而没有苯二氮卓类药物（如地西泮）非特异性调节的常见副作用，因此表明了新的治疗潜力。然而，α5-PAM在临床相关的脑电图（EEG）中是否有可检测到的特征尚不清楚。方法对10只自由活动大鼠进行基线及注射α5-PAM （GL-II-73）和地西泮后的脑电图分析。结果α - 5- pam特异性地降低了θ波峰功率，而地西泮使θ波峰功率由高向低转移，同时增加了α和γ波功率。脑电分解表明，这些影响是周期性的，与θ振荡事件持续时间的变化相对应。结论α5-PAM在啮齿类动物中具有鲁棒性和显著性的脑电图生物标志物，表明脑电图可以实现对α5-PAM治疗效果的无创监测。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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