Abstract：
Mutations in the GATOR1 complex genes, DEPDC5 and NPRL3, play a major role in the development of lesional and non-lesional focal epilepsy through increased mTORC1 signalling. We aimed to assess the effects of mTORC1 hyperactivation on GABAergic inhibitory circuits, in 3 and 5 individuals carrying DEPDC5 and NPRL3 mutations respectively using a multimodal approach including transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy (MRS), and electroencephalography (EEG).
Inhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.
These results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.
Inhibitory functions probed by TMS and MRS showed no effect of mutations on cortical GABAergic receptor-mediated inhibition and GABA concentration, in both cortical and subcortical regions. However, stronger EEG theta oscillations and stronger and more synchronous gamma oscillations were observed in DEPDC5 and NPRL3 mutations carriers.
These results suggest that DEPDC5 and NPRL3-related epileptic mTORopathies may not directly modulate GABAergic functions but are nonetheless characterized by a stronger neural entrainment that may be reflective of a cortical hyperexcitability mediated by increased mTORC1 signaling.
摘要：
背景：GATOR1复杂基因的突变，DEPDC5和NPRL3通过增加mTORC1信号在病灶和非病灶局灶性癫痫的发展中起主要作用。我们旨在评估mTORC1过度激活对GABA能抑制回路的影响，在3个和5个分别携带DEPDC5和NPRL3突变的个体中，使用包括经颅磁刺激（TMS）在内的多模式方法，磁共振波谱（MRS），和脑电图（EEG）。
结果：TMS和MRS探测的抑制功能显示突变对皮质GABA能受体介导的抑制和GABA浓度没有影响，在皮质和皮质下区域。然而,在DEPDC5和NPRL3突变携带者中观察到更强的EEGθ振荡和更强，更同步的伽马振荡。
结论：这些结果表明，DEPDC5和NPRL3相关的癫痫mTORopathy可能不能直接调节GABA能功能，但其特征是更强的神经夹带，这可能反映了由mTORC1信号传导增加介导的皮质过度兴奋。
结果：TMS和MRS探测的抑制功能显示突变对皮质GABA能受体介导的抑制和GABA浓度没有影响，在皮质和皮质下区域。然而,在DEPDC5和NPRL3突变携带者中观察到更强的EEGθ振荡和更强，更同步的伽马振荡。
结论：这些结果表明，DEPDC5和NPRL3相关的癫痫mTORopathy可能不能直接调节GABA能功能，但其特征是更强的神经夹带，这可能反映了由mTORC1信号传导增加介导的皮质过度兴奋。
