Fragile X Syndrome (FXS) is a neurodevelopmental disorder instigated by the absence of a key translation regulating protein, Fragile X Mental Retardation Protein (FMRP). The loss of FMRP in the CNS leads to abnormal synaptic development, disruption of critical periods of plasticity, and an overall deficiency in proper sensory circuit coding leading to hyperexcitable sensory networks. However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Here, we show that in vivo layer 2/3 of the primary somatosensory cortex of the Fmr1 KO mouse exhibits basal hyperexcitability and an increase in neuronal firing rate suppression during whisker activation. This aligns with our in vitro data that indicate an increase in GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired inhibitory plasticity processes. Specifically, we find that mGluR activation sensitivity is overall diminished in the Fmr1 KO mouse leading to both a decreased spontaneous inhibitory postsynaptic input to principal cells and a disrupted form of inhibitory long-term depression (I-LTD). These data suggest an adaptive mechanism that acts to homeostatically counterbalance the cortical hyperexcitability observed in FXS.

译文

脆性X综合征 (FXS) 是一种神经发育障碍,由缺乏关键的翻译调节蛋白,脆性X智力低下蛋白 (FMRP) 引起。CNS中FMRP的丢失会导致突触发育异常,可塑性关键期的破坏以及适当的感觉回路编码的总体缺陷,从而导致过度兴奋的感觉网络。然而,对于这种过度兴奋的环境如何影响抑制性突触可塑性知之甚少。在这里,我们显示fmr1ko小鼠的初级体感皮层的体内层2/3表现出基础的过度兴奋和晶须激活过程中神经元放电速率抑制的增加。这与我们的体外数据一致,这些数据表明gaba能自发活动增加,mGluR介导的抑制输入错误和抑制可塑性过程受损。具体来说,我们发现在Fmr1 KO小鼠中,mGluR激活敏感性总体上降低,从而导致对主要细胞的自发抑制性突触后输入减少和抑制性长期抑郁症 (I-LTD) 的破坏形式。这些数据表明了一种适应性机制,可平衡FXS中观察到的皮质过度兴奋。

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