Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)–CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu₇) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu₇ protein expression in brain tissue from RTT patients and in MECP2-deficient mouse models. In rodents, this reduction impairs mGlu₇-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu₇ activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu₇ positive allosteric modulation decreases apneas in Mecp2^+/− mice, suggesting that mGlu₇ may be a potential therapeutic target for multiple aspects of the RTT phenotype.

Rett 综合征 (RTT) 是一种由甲基 CpG 结合蛋白 2 ( MECP2 ) 基因突变引起的神经发育障碍。在 RTT 小鼠模型中观察到的认知障碍与海马中 Schaffer 侧支 (SC)-CA1 突触的长时程增强 (LTP) 缺陷相关。代谢型谷氨酸受体 7 (mGlu ₇ ) 是成年小鼠 SC-CA1 突触突触前表达的主要 mGlu 受体，它在 GABA 能中间神经元上的激活是诱导 LTP 所必需的。我们证明MECP2中的致病突变降低了 RTT 患者和 MECP2 缺陷小鼠模型脑组织中mGlu ₇蛋白的表达。在啮齿动物中，这种减少会损害 mGlu ₇-介导的突触传递控制。我们表明 mGlu ₇活性的正变构调节可以恢复 LTP 并改善情境恐惧学习、新物体识别和社会记忆。此外，mGlu ₇正变构调节减少了Mecp2 ^+/-小鼠的呼吸暂停，表明 mGlu ₇可能是 RTT 表型多个方面的潜在治疗靶点。