Winsky-Sommerer R, Knapman A, Fedele D E, Schofield C M, Vyazovskiy V V, Rudolph U, Huguenard J R, Fritschy J-M, Tobler I
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, Zurich, Switzerland.
Neuroscience. 2008 Jun 23;154(2):595-605. doi: 10.1016/j.neuroscience.2008.03.081. Epub 2008 Apr 11.
Thalamo-cortical networks generate specific patterns of oscillations during distinct vigilance states and epilepsy, well characterized by electroencephalography (EEG). Oscillations depend on recurrent synaptic loops, which are controlled by GABAergic transmission. In particular, GABA A receptors containing the alpha3 subunit are expressed predominantly in cortical layer VI and thalamic reticular nucleus (nRT) and regulate the activity and firing pattern of neurons in relay nuclei. Therefore, ablation of these receptors by gene targeting might profoundly affect thalamo-cortical oscillations. Here, we investigated the role of alpha3-GABA A receptors in regulating vigilance states and seizure activity by analyzing chronic EEG recordings in alpha3 subunit-knockout (alpha3-KO) mice. The presence of postsynaptic alpha3-GABA A receptors/gephyrin clusters in the nRT and GABA A-mediated synaptic currents in acute thalamic slices was also examined. EEG spectral analysis showed no difference between genotypes during non rapid-eye movement (NREM) sleep or at waking-NREM sleep transitions. EEG power in the spindle frequency range (10-15 Hz) was significantly lower at NREM-REM sleep transitions in mutant compared with wild-type mice. Enhancement of sleep pressure by 6 h sleep deprivation did not reveal any differences in the regulation of EEG activities between genotypes. Finally, the waking EEG showed a slightly larger power in the 11-13-Hz band in alpha3-KO mice. However, neither behavior nor the waking EEG showed alterations suggestive of absence seizures. Furthermore, alpha3-KO mice did not differ in seizure susceptibility in a model of temporal lobe epilepsy. Strikingly, despite the disruption of postsynaptic gephyrin clusters, whole-cell patch clamp recordings revealed intact inhibitory synaptic transmission in the nRT of alpha3-KO mice. These findings show that the lack of alpha3-GABA(A) receptors is extensively compensated for to preserve the integrity of thalamo-cortical function in physiological and pathophysiological situations.
丘脑 - 皮质网络在不同的警觉状态和癫痫发作期间会产生特定的振荡模式，这可以通过脑电图（EEG）很好地进行表征。振荡依赖于反复的突触回路，而这些回路受GABA能传递的控制。特别是，含有α3亚基的GABA A受体主要在皮质第VI层和丘脑网状核（nRT）中表达，并调节中继核中神经元的活动和放电模式。因此，通过基因靶向消除这些受体会深刻影响丘脑 - 皮质振荡。在此，我们通过分析α3亚基敲除（α3-KO）小鼠的慢性EEG记录，研究了α3-GABA A受体在调节警觉状态和癫痫活动中的作用。我们还检查了急性丘脑切片中nRT中突触后α3-GABA A受体/桥连蛋白簇的存在以及GABA A介导的突触电流。EEG频谱分析表明，在非快速眼动（NREM）睡眠期间或从清醒到NREM睡眠转换时，不同基因型之间没有差异。与野生型小鼠相比，突变小鼠在NREM - REM睡眠转换时纺锤体频率范围（10 - 15Hz）的EEG功率显著降低。6小时睡眠剥夺增加睡眠压力后，不同基因型在EEG活动调节方面未显示出任何差异。最后，清醒EEG显示α3-KO小鼠在11 - 13Hz频段的功率略大。然而，行为和清醒EEG均未显示出提示失神发作存在的改变。此外，在颞叶癫痫模型中，α3-KO小鼠的癫痫易感性没有差异。令人惊讶的是，尽管突触后桥连蛋白簇受到破坏，但全细胞膜片钳记录显示α3-KO小鼠nRT中的抑制性突触传递完整。这些发现表明，在生理和病理生理情况下，α3-GABA(A)受体的缺失得到了广泛的代偿，以维持丘脑 - 皮质功能的完整性。
