Division of Biomedical Sciences, School of Medicine, University of California, Riverside, USA.
Division of Child and Adolescent Psychiatry, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
J Neurodev Disord. 2022 Sep 27;14(1):52. doi: 10.1186/s11689-022-09455-9.
Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS.
In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABA selective agonist racemic baclofen (RBAC).
In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted.
Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field.
The human experiments are registered under NCT02998151.
脆性 X 综合征（FXS）是最常见的遗传性神经发育障碍。它通常表现为智力障碍、焦虑、重复行为、社交沟通障碍、语言发育迟缓以及异常的感觉处理，尤其是在男性中。最近，我们发现了 FXS 小鼠模型（Fmr1 KO 小鼠）和 FXS 患者之间保守的脑电图（EEG）生物标志物。
在本报告中，我们评估了小分子的靶点结合情况，利用多电极阵列电生理学在 Fmr1 KO 小鼠和 FXS 患者中进行评估。神经生理靶点结合通过单次使用 GABA 选择性激动剂消旋巴氯芬（RBAC）进行评估。
在 Fmr1 KO 小鼠和 FXS 患者中，巴氯芬的使用与静息状态下γ功率升高的抑制和低频功率的增加有关。在 Fmr1 KO 小鼠中，还观察到巴氯芬与听觉啁啾同步性的改善有关。
总的来说，我们注意到 RBAC 在 FXS 中跨物种对静息状态下电生理学的靶向结合，特别是减少异常的高频γ活动。这一发现为 FXS 的药物开发提供了转化医学方法的希望，通过在该领域中使用成熟的 EEG 生物标志物，在跨物种中同步治疗研究。
人类实验在 NCT02998151 下注册。
