Changes in excitation and inhibition are associated with the pathobiology of neurodevelopmental disorders of intellectual disability and autism and are widely described in Fragile X syndrome (FXS). In the prefrontal cortex (PFC), essential for cognitive processing, excitatory connectivity and plasticity are found altered in the FXS mouse model, however, little is known about the state of inhibition. To that end, we investigated GABAergic signaling in the Fragile X Mental Retardation 1 (FMR1) knock out (Fmr1-KO) mouse medial PFC (mPFC). We report changes at the molecular, and functional levels of inhibition at three (prepubescence) and six (adolescence) postnatal weeks. Functional changes were most prominent during early postnatal development, resulting in stronger inhibition, through increased synaptic inhibitory drive and amplitude, and reduction of inhibitory short-term synaptic depression. Noise analysis of prepubescent post-synaptic currents demonstrated an increased number of receptors opening during peak current in Fmr1-KO inhibitory synapses. During adolescence amplitudes and plasticity changes normalized, however, the inhibitory drive was now reduced in Fmr1-KO, while synaptic kinetics were prolonged. Finally, adolescent GABA_A receptor subunit α2 and GABA_B receptor subtype B1 expression levels were different in Fmr1-KOs than WT littermate controls. Together these results extend the degree of synaptic GABAergic alterations in FXS, now to the mPFC of Fmr1-KO mice, a behaviourally relevant brain region in neurodevelopmental disorder pathology.

兴奋和抑制的变化与智力障碍和自闭症的神经发育障碍的病理生物学有关，并且在脆性X综合征（FXS）中得到了广泛描述。在前额叶皮层（PFC）中，发现认知过程，兴奋性连接性和可塑性在FXS小鼠模型中发生了变化，但是对于抑制状态知之甚少。为此，我们研究了脆性X智力发育迟缓1（FMR1）敲除（Fmr1-KO）小鼠内侧PFC（mPFC）中的GABA能信号。我们报告了在产后三周（青春期前）和六周（青春期）抑制分子和功能水平的变化。在产后早期阶段，功能变化最为明显，通过增加突触抑制驱动力和振幅来产生更强的抑制作用，和减少抑制性短期突触抑制。青春期前突触后电流的噪声分析表明，在Fmr1-KO抑制突触的峰值电流过程中，打开的受体数量增加。在青春期，振幅和可塑性变化正常化，但是，Fmr1-KO的抑制驱动力现在降低了，而突触动力学却延长了。最后，青春期GABAFmr1-KOs中_的受体亚基α2和GABA _B受体亚型B1的表达水平与野生同窝对照相比有所不同。这些结果加在一起，将FXS的突触GABA能改变的程度扩展到了Fmr1-KO小鼠的mPFC，Fmr1-KO小鼠是神经发育障碍病理学中行为相关的大脑区域。