Dong Hong-Wei, Weiss Kelly, Dickerson Jonathan W, Meadows Mac J, Zagol-Ikapitte Irene, Boutaud Olivier, Rook Jerri M, Neul Jeffrey L, Niswender Colleen M
Division of Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt University Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, School of Medicine, Vanderbilt University, Nashville, Tennessee.
J Pharmacol Exp Ther. 2025 Jun;392(6):103602. doi: 10.1016/j.jpet.2025.103602. Epub 2025 May 8.
Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Genetic restoration of MECP2 in mice can reverse phenotypes, providing hope for disease-modifying therapies in the disease. Studies in people with and mouse models of RTT have identified neurophysiological features, such as auditory event-related potentials (AEPs), that correlate with disease severity, suggesting potential as translatable biomarkers. We have identified reductions in the expression and function of the group III metabotropic glutamate receptor 7 (mGlu), a G protein-coupled receptor regulating presynaptic neurotransmitter release, in both human and mouse RTT brains. Additionally, treatment of RTT mice with a positive allosteric modulator (PAM) of the group III mGlu receptors (VU0422288) improves behavioral phenotypes, most likely via mGlu potentiation. To evaluate whether VU0422288 treatment modulates neurophysiological biomarkers, we acutely treated RTT mice with VU0422288 at 3,10, and 30 mg/kg and assessed neurophysiological features. VU0422288 treatment caused increases in AEP peak amplitudes in RTT mice but not in wild-type controls, with no effect on basal electroencephalogram power. Treatment with a different compound, ADX88178, a PAM that activates the mGlu receptors, did not affect neurophysiological assessments, suggesting that the target of VU0422288 is likely mGlu. These findings suggest that neurophysiological features, like AEP, have potential as sensitive and quantitative biomarkers that may be useful in evaluating mGlu PAMs and other pharmacological interventions as novel RTT treatment strategies. SIGNIFICANCE STATEMENT: Correlations between neurophysiological features and disease severity in Rett syndrome suggest their potential as translatable biomarkers sensitive to pharmacological modulation. This study demonstrates that potentiation of group III metabotropic glutamate receptors improves neurophysiological features in Rett syndrome mice.
瑞特综合征（RTT）是一种神经发育障碍，主要由X连锁甲基化CpG结合蛋白2（MECP2）基因的功能丧失突变引起。在小鼠中对MECP2进行基因修复可以逆转表型，为该疾病的疾病修饰疗法带来了希望。对瑞特综合征患者和小鼠模型的研究已经确定了与疾病严重程度相关的神经生理特征，如听觉事件相关电位（AEP），这表明其有作为可转化生物标志物的潜力。我们已经确定，在人类和小鼠的瑞特综合征大脑中，III组代谢型谷氨酸受体7（mGlu）的表达和功能降低，mGlu是一种调节突触前神经递质释放的G蛋白偶联受体。此外，用III组mGlu受体的正变构调节剂（PAM）（VU0422288）治疗瑞特综合征小鼠可改善行为表型，最有可能是通过增强mGlu来实现的。为了评估VU0422288治疗是否能调节神经生理生物标志物，我们以3、10和30mg/kg的剂量对瑞特综合征小鼠进行VU0422288急性治疗，并评估神经生理特征。VU0422288治疗使瑞特综合征小鼠的AEP峰振幅增加，但对野生型对照无影响，对基础脑电图功率也无影响。用另一种化合物ADX88178（一种激活mGlu受体的PAM）进行治疗，对神经生理评估没有影响，这表明VU0422288的靶点可能是mGlu。这些发现表明，像AEP这样的神经生理特征有潜力作为敏感和定量的生物标志物，可能有助于评估mGlu PAM和其他药理学干预措施作为新型瑞特综合征治疗策略的效果。意义声明：瑞特综合征中神经生理特征与疾病严重程度之间的相关性表明它们有作为对药理学调节敏感的可转化生物标志物的潜力。本研究表明，增强III组代谢型谷氨酸受体可改善瑞特综合征小鼠的神经生理特征。
