Research press release


Nature Neuroscience

Inhibitory neurons drive Rett Syndrome symptoms



Zhaolan Zhouたちの報告によると、マウスで前脳のGABA作動性阻害性ニューロンという特定のニューロンで特異的にMeCP2を削除するだけで、この疾患に伴う聴覚障害と発作が繰り返し現れる。ところが、グルタミン酸作動性興奮性ニューロンという他の種類のニューロンからこの遺伝子を削除しても、この結果は現れない。加えて、阻害性ニューロンで「正常な」MeCP2発現に置換するだけで、そのマウスの聴覚経路が回復し発作が改善する。なぜMeCP2発現がGABA作動性阻害性ニューロンで特異的に必要なのか、また、これらニューロンが感覚消失や発作の発生に厳密にはどのように寄与するのかは全く明らかではない。

The specific loss of function of the protein MeCP2 in inhibitory neurons in the forebrains of mice drives the onset of sensory deficits and seizures reported in Rett Syndrome, finds a paper published this week in Nature Neuroscience. This study provides important insight into the identity of the cells, which appear to mediate many of the debilitating symptoms associated with Rett Syndrome, and suggests that strategies aimed at replacing MeCP2 in these neurons might be a viable therapeutic approach.

Rett Syndrome is a neurodevelopmental disorder that is believed to result from mutations in the gene MeCP2. Symptoms of Rett Syndrome include small head and brain size, breathing abnormalities, intellectual disability, seizures and sensory (auditory and/or visual) deficits.

Zhaolan Zhou and colleagues report that deleting MeCP2 specifically in one class of neurons, the forebrain GABAergic inhibitory interneurons, in mice is sufficient to recapitulate the auditory disturbances and seizures that are associated with the disease. However, deleting the gene from another class of neurons, excitatory glutamatergic neurons, did not show this result. In addition, replacing ‘normal’ MeCP2 expression in the inhibitory neurons is sufficient to restore auditory processing and ameliorate seizures in these animals. It is not entirely clear why MeCP2 expression is necessary specifically in GABAergic inhibitory neurons or precisely how these neurons contribute to sensory deficits and seizure generation.

doi: 10.1038/nn.3710

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