The Jackson Laboratory, Bar Harbor, Maine 04609.
J Neurosci. 2014 Feb 12;34(7):2754-63. doi: 10.1523/JNEUROSCI.4900-12.2014.
Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability.
MECP2 基因突变会导致雷特综合征（RTT），这是一种神经发育障碍，导致运动和认知功能丧失、社交互动受损以及在年轻时发生癫痫。神经元回路发育和功能缺陷被认为是 RTT 症状的原因。大多数 RTT 患者会出现复发性癫痫，表明神经元过度兴奋是 RTT 的一个常见特征。然而，RTT 中过度兴奋的机制尚未完全了解。在这里，我们表明在小鼠中从皮质兴奋性神经元而不是从大脑前皮质抑制性神经元中删除 Mecp2 会导致自发性癫痫。选择性地从大脑前皮质的兴奋性神经元而不是抑制性神经元中删除 Mecp2 会降低前额叶和体感皮层中 5 层锥体神经元中的 GABA 能传递。从皮质兴奋性神经元中丢失 MeCP2 会减少皮质中的 GABA 能突触数量，并增强 5 层锥体神经元的兴奋性。使用在 2/3 层锥体神经元中进行的单细胞删除 Mecp2，我们表明没有 MeCP2 的神经元中的 GABA 能传递减少，但具有 MeCP2 的相邻神经元中的 GABA 能传递是正常的。这些结果表明，皮质兴奋性神经元中的 MeCP2 在调节 GABA 能传递和皮质兴奋性方面发挥着关键作用。
