Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia Health System, Charlottesville, VA 22908, USA.
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Neurobiol Dis. 2017 Dec;108:183-194. doi: 10.1016/j.nbd.2017.08.018. Epub 2017 Aug 30.
Temporal lobe epilepsy (TLE) is a common form of adult epilepsy involving the limbic structures of the temporal lobe. Subiculum neurons act to provide a major output from the hippocampus and consist of a large population of endogenously bursting excitatory neurons. In TLE, subiculum neurons are largely spared, become hyperexcitable and show spontaneous epileptiform activity. The basis for this hyperexcitability is unclear, but is likely to involve alterations in the expression levels and function of various ion channels. In this study, we sought to determine the importance of sodium channel currents in facilitating neuronal hyperexcitability of subiculum neurons in the continuous hippocampal stimulation (CHS) rat model of TLE. Subiculum neurons from TLE rats were hyperexcitable, firing a higher frequency of action potentials after somatic current injection and action potential (AP) bursts after synaptic stimulation. Voltage clamp recordings revealed increases in resurgent (I) and persistent (I) sodium channel currents and pro-excitatory shifts in sodium channel activation and inactivation parameters that would facilitate increases in AP generation. Attenuation of I and I currents with 4,9-anhydro-tetrodotoxin (4,9-ah TTX; 100nM), a toxin with increased potency against Na1.6 channels, suppressed neuronal firing frequency and inhibited AP bursting induced by synaptic stimulation in TLE neurons. These findings support an important role of sodium channels, particularly Na1.6, in facilitating subiculum neuron hyperexcitability in TLE and provide further support for the importance of I and I currents in establishing epileptiform activity of subiculum neurons.
颞叶癫痫（TLE）是一种常见的成人癫痫形式，涉及颞叶的边缘结构。海马下托神经元作为海马的主要输出，包含大量内源性爆发兴奋性神经元。在 TLE 中，海马下托神经元在很大程度上未受影响，但变得过度兴奋，并表现出自发性癫痫样活动。这种过度兴奋的基础尚不清楚，但可能涉及各种离子通道表达水平和功能的改变。在这项研究中，我们试图确定钠通道电流在促进 TLE 连续海马刺激（CHS）大鼠模型中海马下托神经元的神经元过度兴奋中的重要性。TLE 大鼠的海马下托神经元过度兴奋，在体电流注入后，动作电位（AP）爆发后的放电频率更高，突触刺激后的动作电位爆发。电压钳记录显示，再生（I）和持续（I）钠电流增加，钠通道激活和失活参数的促兴奋转移，这将促进 AP 产生的增加。用 4,9-脱水四氢毒蕈碱（4,9-ah TTX；100nM）抑制 I 和 I 电流，4,9-ah TTX 是一种对 Na1.6 通道具有更高效力的毒素，可抑制 TLE 神经元的放电频率，并抑制突触刺激诱导的 AP 爆发。这些发现支持钠通道，特别是 Na1.6，在促进 TLE 中海马下托神经元过度兴奋中的重要作用，并进一步支持 I 和 I 电流在建立海马下托神经元癫痫样活动中的重要性。
