Karimzadeh Fariba, Modarres Mousavi Sayed Mostafa, Alipour Fatemeh, Hosseini Ravandi Hassan, Kovac Stjepana, Gorji Ali
Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.
Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
Brain Struct Funct. 2017 Aug;222(6):2773-2785. doi: 10.1007/s00429-017-1371-9. Epub 2017 Feb 16.
Childhood absence epilepsy (CAE) is an epilepsy syndrome with seizures occurring in the early childhood, highlighting that seizures susceptibility in CAE is dependent on brain development. The Notch 1 signalling pathway is important in brain development, yet the role of the Notch1 signalling pathway in CAE remains elusive. We here explored Notch1 and its modulator notchless homologue 1 (NLE1) expression in WAG/Rij and control rats using immunohistochemistry. Functional Notch 1 effects were assessed in WAG/Rij rats in vivo. WAG/Rij rats lack the developmental increase in cortical Notch1 and NLE 1 mRNA expression seen in controls, and Notch 1 and NLE1 mRNA and protein expression were lower in somatosensory cortices of WAG/Rij rats when compared to controls. This coincided with an overall decreased cortical GFAP expression in the early development in WAG/Rij rats. These effects were region-specific as they were not observed in thalamic tissues. Neuron-to-glia ratio as a marker of the impact of Notch signalling on differentiation was higher in layer 4 of somatosensory cortex of WAG/Rij rats. Acute application of Notch 1 agonist Jagged 1 suppressed, whereas DAPT, a Notch antagonist, facilitated spike and wave discharges (SWDs) in WAG/Rij rats. These findings point to Notch1 as an important signalling pathway in CAE which likely shapes architectural organization of the somatosensory cortex, a region critically involved in developmental epileptogenesis in CAE. More immediate effects of Notch 1 signalling are seen on in vivo SWDs in CAE, pointing to the Notch 1 pathway as a possible treatment target in CAE.
儿童失神癫痫（CAE）是一种癫痫综合征，其发作始于儿童早期，这突出表明CAE的癫痫易感性取决于大脑发育。Notch 1信号通路在大脑发育中很重要，然而Notch1信号通路在CAE中的作用仍不清楚。我们在这里使用免疫组织化学方法研究了WAG/Rij大鼠和对照大鼠中Notch1及其调节因子无Notch同源物1（NLE1）的表达。在WAG/Rij大鼠体内评估了功能性Notch 1的作用。WAG/Rij大鼠缺乏对照组中所见的皮质Notch1和NLE 1 mRNA表达的发育性增加，与对照组相比，WAG/Rij大鼠体感皮层中Notch 1和NLE1 mRNA及蛋白表达较低。这与WAG/Rij大鼠早期发育中皮质GFAP表达总体下降相一致。这些效应具有区域特异性，因为在丘脑组织中未观察到。作为Notch信号对分化影响的标志物，WAG/Rij大鼠体感皮层第4层的神经元与胶质细胞比率较高。急性应用Notch 1激动剂Jagged 1可抑制WAG/Rij大鼠的棘波和慢波放电（SWDs），而Notch拮抗剂DAPT则可促进其放电。这些发现表明Notch1是CAE中的一条重要信号通路，它可能塑造了体感皮层的结构组织，而体感皮层是CAE发育性癫痫发生中至关重要的一个区域。在CAE中，Notch 1信号对体内SWDs有更直接的影响，这表明Notch 1通路可能是CAE的一个治疗靶点。
