Department of Pharmacology, University of Virginia, Charlottesville, United States.
Department of Neurosurgery, Massachusetts General Hospital, Boston, United States.
Elife. 2020 Sep 9;9:e59548. doi: 10.7554/eLife.59548.
Absence seizures result from 3 to 5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel gating on GABA receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABA receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate inhibition kinetics.
失神发作是由 3 至 5 Hz 的全脑性丘脑皮质振荡引起的，这依赖于丘脑内高度调节的抑制性神经传递。有效摄取抑制性神经递质 GABA 是至关重要的，摄取失败会加重人类癫痫发作。在这里，我们表明，在包含丘脑皮质癫痫网络关键部分的急性大鼠脑片中阻断 GABA 转运体 (GATs) 会调节癫痫样活动。正如预期的那样，我们发现阻断 GAT1 或 GAT3 均可延长振荡。然而，出乎意料的是，阻断两者均会抑制振荡。将实验观察结果整合到单个神经元和网络级计算模型中，说明了 T 型钙通道门控对 GABA 受体活性的非线性依赖性如何调节网络振荡。T 型通道的开启对于维持振荡是必需的，但 GABA 受体活性过短或过长都不足以充分打开 T 型通道。只有在狭窄的范围内，延长 GABA 受体活性才能促进通道开放并加剧振荡。这些结果对调节抑制动力学的治疗方法具有重要意义。
