Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy. This model uniquely enables the in vivo characterization and rescue of the electrographic seizures associated with TSC. We demonstrate that inhibition of mGluR5 corrects hyperactivity, seizures, and elevated de novo synaptic protein synthesis. Conversely, positive allosteric modulation of mGluR5 results in the exacerbation of hyperactivity and epileptic phenotypes. The data suggest a meaningful therapeutic potential for mGluR5 NAMs in TSC, which warrants clinical exploration and the continued development of mGluR5 therapies.

中文翻译：

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mGluR5在结节性硬化症小鼠模型中行为和癫痫表型的调节。

靶向代谢型谷氨酸受体5（mGluR5）的药物在包括结节性硬化症（TSC）在内的自闭症谱系障碍（ASD）中具有治疗潜力。除其他因素外，抑制或增强mGluR5是否有益的问题取决于具体适应症。为促进mGluR5治疗策略的发展，我们使用了具有Tsc2神经元缺失的突变小鼠模型来测试mGluR5负向和正向变构调节剂（mGluR5 NAM和PAM）对TSC的治疗效用，该小鼠模型证明了与疾病相关的表型，包括行为自闭症和癫痫的症状。该模型独特地实现了与TSC相关的电图发作的体内表征和挽救。我们证明了对mGluR5的抑制作用可纠正机能亢进，癫痫发作，和从头突触蛋白合成的增加。相反，mGluR5的正变构调节导致机能亢进和癫痫表型加重。数据表明mGluR5 NAM在TSC中具有有意义的治疗潜力，值得临床探索和继续开发mGluR5疗法。