Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
Commun Biol. 2024 Feb 23;7(1):225. doi: 10.1038/s42003-024-05907-1.
Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABA receptor (α5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of α5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of α5-PAM on tonic inhibition as measured in human neurons, and tested in silico α5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that α5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an α5-PAM dose-response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate α5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.
表达生长抑素的中间神经元抑制作用减弱与抑郁有关。在慢性应激的啮齿动物模型中，给予选择性针对这种缺失抑制的α5 亚单位包含 GABA 受体的正变构调节剂（α5-PAM），可表现出抗抑郁和认知促进作用。然而，α5-PAM 在人类大脑中的功能影响尚不清楚，目前也无法通过实验进行评估。我们模拟了α5-PAM 对人体神经元中测量的紧张性抑制的影响，并在健康和抑郁的人类皮质微循环详细模型中进行了计算机模拟 α5-PAM 作用。我们发现，α5-PAM 可以有效恢复刺激检测指标量化的受损皮质处理，还可以恢复微电路 EEG 信号的功率谱密度分布。我们进行了 α5-PAM 剂量反应，并确定了模拟 EEG 生物标志物候选物。我们的研究结果有助于降低风险并促进 α5-PAM 的转化，并提供非侵入性脑信号中的生物标志物，用于监测靶标结合和药物疗效。
