Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus.

IF 4.6 3区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Gene Therapy Pub Date : 2024-10-25 DOI:10.1038/s41434-024-00493-7
Ana Gonzalez-Ramos, Fredrik Berglind, Jan Kudláček, Elza R Rocha, Esbjörn Melin, Ana M Sebastião, Cláudia A Valente, Marco Ledri, My Andersson, Merab Kokaia
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Abstract

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

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PSAM4-GlyR的化学遗传降低了癫痫海马的兴奋性和痫样活动。
尽管近年来临床上出现了一些新药,但耐药性癫痫仍然是医疗保健领域尚未解决的难题,三分之一的癫痫患者仍然对抗癫痫药物难治。实验模型中的基因疗法已成为针对致痫灶中特定神经元群的有效治疗方法。当利用化学遗传学与外部化学激活剂相结合时,它还能成为一种 "按需 "治疗方法。在这里,我们评估了一种有针对性的特异性化学遗传疗法--PSAM/PSEM 系统,它有望成为临床应用于治疗耐药性癫痫的潜在候选疗法。我们发现,惰性配体 uPSEM817 可选择性地激活氯离子渗透通道 PSAM4-GlyR,从而有效减少体外去极化诱导的动作电位数量。这种效应可能是由于去极化电流的分流,这些细胞膜阻抗的降低证明了这一点。在器官型切片中,uPSEM817 可减少自发性癫痫样活动的爆发次数和峰值振幅。虽然在雄性小鼠颞叶癫痫模型中,体内施用 uPSEM817 并未显著改变电图癫痫发作,但它确实显示出降低发作间期癫痫样放电频率的强烈趋势。这些研究结果表明,基于 PSAM4-GlyR 的化学遗传学具有作为抗癫痫策略的潜力,尽管还需要进一步改进以提高其疗效。
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来源期刊
Gene Therapy
Gene Therapy 医学-生化与分子生物学
CiteScore
9.70
自引率
2.00%
发文量
67
审稿时长
4-8 weeks
期刊介绍: Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
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