Rett syndrome and MECP2 Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding methyl-CpG-binding protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu7) in a mouse model of Rett syndrome. Positive allosteric modulation of mGlu7 activity was sufficient to improve several disease phenotypes including cognition. Here, we tested the hypothesis that mGlu7 expression would be reciprocally regulated in a mouse model of MECP2 Duplication syndrome, such that negative modulation of mGlu7 activity would exert therapeutic benefit. To the contrary, we report that mGlu7 is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu7 activity impacts phenotypes that are antiparallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu7 expression and function is affected by changes in MeCP2 dosage and have important implications for the therapeutic development of mGlu7 modulators.

中文翻译：

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遗传还原或负调控的mGlu7不会影响焦虑和恐惧学习表型的MECP2复制综合征的小鼠模型中。

Rett综合征和MECP2复制综合征是神经发育障碍，分别归因于编码甲基CpG结合蛋白2（MeCP2）的基因的功能丧失突变或重复。我们最近报道了在Rett综合征的小鼠模型中代谢型谷氨酸受体7（mGlu7）的表达和功能降低。mGlu7活性的正变构调节足以改善包括认知在内的几种疾病表型。在这里，我们测试了以下假设：在MECP2复制综合征的小鼠模型中，mGlu7的表达将受到相互调节，因此mGlu7活性的负调控将发挥治疗作用。相反的，我们报告说，在过表达MeCP2的小鼠中，mGlu7的功能并未增加，并且既不遗传也不降低mGlu7活性的药理学影响的表型与在Rett综合征模型小鼠中观察到的反平行。这些数据扩展了我们对MeG2剂量变化如何影响mGlu7表达和功能的理解，并对mGlu7调节剂的治疗发展具有重要意义。