Department of Neurology, Baylor College of Medicine, Houston, Texas, USA.
Epilepsia. 2009 Jul;50(7):1741-51. doi: 10.1111/j.1528-1167.2009.02086.x. Epub 2009 May 11.
Kv4.2 subunits contribute to the pore-forming region of channels that express a transient, A-type K(+) current (A-current) in hippocampal CA1 pyramidal cell dendrites. Here, the A-current plays an important role in signal processing and synaptic integration. Kv4.2 knockout mice show a near elimination of the A-current in area CA1 dendrites, producing increased excitability in this region. In these studies, we evaluated young adult Kv4.2 knockout mice for spontaneous seizures and the response to convulsant stimulation in the whole animal in vivo and in hippocampal slices in vitro.
Electroencephalogram electrode-implanted Kv4.2 knockout and wild-type mice were observed for spontaneous behavioral and electrographic seizures. The latency to seizure and status epilepticus onset in Kv4.2 knockout and wild-type mice was assessed following intraperitoneal injection of kainate. Extracellular field potential recordings were performed in hippocampal slices from Kv4.2 knockout and wild-type mice following the bath application of bicuculline.
No spontaneous behavioral or electrographic seizures were observed in Kv4.2 knockout mice. Following kainate, Kv4.2 knockout mice demonstrated a decreased seizure and status epilepticus latency as well as increased mortality compared to wild-type littermates. The background strain modified the seizure susceptibility phenotype in Kv4.2 knockout mice. In response to bicuculline, slices from Kv4.2 knockout mice exhibited an increase in epileptiform bursting in area CA1 as compared to wild-type littermates.
These studies show that loss of Kv4.2 channels is associated with enhanced susceptibility to convulsant stimulation, supporting the concept that Kv4.2 deficiency may contribute to aberrant network excitability and regulate seizure threshold.
Kv4.2 亚基构成了表达在海马 CA1 锥体神经元树突中瞬时 A 型钾电流（A 电流）的通道的孔形成区。在此，A 电流在信号处理和突触整合中起重要作用。Kv4.2 敲除小鼠在 CA1 树突区几乎消除了 A 电流，导致该区域兴奋性增加。在这些研究中，我们在体内整体动物和体外海马切片中评估了年轻成年 Kv4.2 敲除小鼠的自发性癫痫发作以及对惊厥刺激的反应。
植入脑电图电极的 Kv4.2 敲除和野生型小鼠被观察自发的行为和脑电图癫痫发作。通过腹腔内注射海人酸评估 Kv4.2 敲除和野生型小鼠的癫痫发作潜伏期和癫痫持续状态发作。在灌流应用荷包牡丹碱后，从 Kv4.2 敲除和野生型小鼠的海马切片中进行细胞外场电位记录。
在 Kv4.2 敲除小鼠中未观察到自发的行为或脑电图癫痫发作。在海人酸之后，与野生型同窝仔相比，Kv4.2 敲除小鼠的癫痫发作和癫痫持续状态潜伏期缩短，死亡率增加。背景品系修饰了 Kv4.2 敲除小鼠的癫痫易感性表型。在荷包牡丹碱的反应中，与野生型同窝仔相比，Kv4.2 敲除小鼠的 CA1 区出现更多的癫痫样爆发。
这些研究表明，Kv4.2 通道的缺失与惊厥刺激的易感性增强有关，支持 Kv4.2 缺乏可能导致异常网络兴奋性增加并调节癫痫发作阈值的概念。
