Montreal Neurological Institute and Hospital, Departments of Neurology & Neurosurgery and of Physiology, McGill University, 3801 University Street, Montreal, H3A 2B4, QC, Canada.
Montreal Neurological Institute and Hospital, Departments of Neurology & Neurosurgery and of Physiology, McGill University, 3801 University Street, Montreal, H3A 2B4, QC, Canada.
Neuropharmacology. 2020 May 1;167:107982. doi: 10.1016/j.neuropharm.2020.107982. Epub 2020 Jan 31.
γ-Aminobutyric acid (GABA), which is released by interneurons, plays an active role in generating interictal epileptiform spikes during blockade of ionotropic glutamatergic signalling, but it remains unclear whether and how the K-Cl cotransporter 2 (KCC2) influences these paroxysmal events. Therefore, we employed tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced interictal spikes that were pharmacologically isolated by applying ionotropic glutamatergic receptor antagonists. After the addition of VU0463271, these interictal spikes continued to occur at similar rates as in control (i.e., during application of 4AP with ionotropic glutamatergic receptor antagonists) but were smaller and shorter. Despite the absence of ionotropic glutamatergic receptor signalling, both interneurons and principal cells increased their firing during interictal spikes. Moreover, we found that KCC2 antagonism increased interneuron firing but decreased principal cell firing during the interictal spike rising phase; in contrast, during the falling phase, interneuron firing decreased in the presence of VU0463271 while no change was observed in principal cell firing. Overall, our results show that KCC2 antagonism enhances interneuron excitability at the onset of interictal spikes generated by the EC neuronal networks during blockade of ionotropic glutamatergic transmission but disrupts later neuronal recruitment.
γ-氨基丁酸（GABA）由中间神经元释放，在离子型谷氨酸能信号阻断时对产生发作间期癫痫样尖峰发挥积极作用，但 K-Cl 协同转运蛋白 2（KCC2）是否以及如何影响这些阵发性事件仍不清楚。因此，我们在体外大鼠内嗅皮层（EC）中使用四极管记录来分析 KCC2 拮抗剂 VU0463271 对 4-氨基吡啶（4AP）诱导的发作间期尖峰的影响，这些尖峰通过应用离子型谷氨酸能受体拮抗剂在药理学上被分离出来。在添加 VU0463271 后，这些发作间期尖峰继续以与对照相似的速率发生（即在应用离子型谷氨酸能受体拮抗剂和 4AP 时），但幅度较小且持续时间较短。尽管没有离子型谷氨酸能受体信号，中间神经元和主细胞在发作间期尖峰期间均增加了放电。此外，我们发现 KCC2 拮抗作用增加了发作间期尖峰上升相期间中间神经元的放电，但降低了主细胞的放电；相反，在下降相期间，在存在 VU0463271 的情况下，中间神经元的放电减少，而主细胞的放电没有变化。总体而言，我们的结果表明，在离子型谷氨酸能传递阻断时，KCC2 拮抗作用增强了 EC 神经元网络产生的发作间期尖峰起始时中间神经元的兴奋性，但破坏了随后的神经元募集。
