Gabel L A, Nisenbaum E S
Department of Psychology, University of Connecticut, Storrs, Connecticut 06269, USA.
J Neurophysiol. 1998 Apr;79(4):1989-2002. doi: 10.1152/jn.1998.79.4.1989.
Neostriatal spiny projection neurons can display a pronounced delay in their transition to action potential discharge that is mediated by a slowly developing ramp depolarization. The possible contribution of a slowly inactivating A-type K+ current (IAs) to this delayed excitation was investigated by studying the biophysical and functional properties of IAs using whole cell voltage- and current-clamp recording from acutely isolated neostriatal neurons. Isolation of IAs from other voltage-gated, calcium-independent K+ currents was achieved through selective blockade of IAs with low concentrations (10 microM) of the benzazepine derivative, 6-chloro-7,8-dihydroxy-3-allyl- 1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepine (APB; SKF82958) and subsequent current subtraction. Examination of the voltage dependence of activation showed that IAs began to flow at approximately -60 mV in response to depolarization. The voltage dependence of inactivation revealed that approximately 50% of IAs channels were available at the normal resting potential (-80 mV) of these cells, but that only 20% of the channels were available at membrane potentials corresponding to spike threshold (about -40 mV). At these depolarized membrane potentials, the rate of activation was moderately rapid (tau approximately 60 ms), whereas the rate of inactivation was slow (tau approximately 1.5 s). The time course of removal of inactivation of IAs at -80 mV also was relatively slow (tau approximately 1.0 s). The subthreshold availability of IAs combined with its rapid activation and slow inactivation rates suggested that this current should be capable of dampening the onset of prolonged depolarizing responses, but over time its efficacy should diminish, slowly permitting the membrane to depolarize toward spike threshold. Voltage recording experiments confirmed this hypothesis by demonstrating that application of APB at a concentration (10 microM) that selectively blocks IAs substantially decreased the latency to discharge and increased the frequency of firing of neostriatal neurons. The properties of IAs suggest that it should play a critical role in placing the voltage limits on the recurring episodes of subthreshold depolarization which are characteristic of spiny neurons recorded in vivo. However, the voltage dependence and recovery kinetics of inactivation of IAs predict that its effectiveness will vary exponentially with the level and duration of hyperpolarization which precedes depolarizing episodes. Thus long periods of hyperpolarization should increase the availability of IAs and dampen succeeding depolarizations; whereas brief epochs of hyperpolarization should not sufficiently remove inactivation of IAs, thereby reducing its ability to limit subsequent depolarizing responses.
新纹状体棘状投射神经元在向动作电位发放转变时可表现出明显延迟，这一延迟由缓慢发展的斜坡去极化介导。通过使用急性分离的新纹状体神经元的全细胞电压钳和电流钳记录来研究缓慢失活的A 型钾电流（IAs）对这种延迟兴奋的可能作用，从而探究IAs的生物物理和功能特性。通过用低浓度（10微摩尔）的苯并氮杂卓衍生物6-氯-7,8-二羟基-3-烯丙基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓（APB；SKF82958）选择性阻断IAs并随后进行电流减法，实现了从其他电压门控、非钙依赖性钾电流中分离出IAs。对激活的电压依赖性检查表明，IAs在去极化时约在-60毫伏开始流动。失活的电压依赖性表明，在这些细胞的正常静息电位（-80毫伏）时，约50%的IAs通道可用，但在对应于动作电位阈值的膜电位（约-40毫伏）时，只有20%的通道可用。在这些去极化的膜电位下，激活速率适中较快（时间常数约60毫秒），而失活速率较慢（时间常数约1.5秒）。在-80毫伏时IAs失活去除的时间进程也相对较慢（时间常数约1.0秒）。IAs的阈下可用性及其快速激活和缓慢失活速率表明，这种电流应能够抑制延长的去极化反应的起始，但随着时间推移其功效应会降低，从而缓慢地使膜朝着动作电位阈值去极化。电压记录实验通过证明以选择性阻断IAs的浓度（10微摩尔）应用APB可显著缩短新纹状体神经元的发放潜伏期并增加其发放频率，证实了这一假设。IAs的特性表明，它在为体内记录的棘状神经元特有的阈下去极化反复发作设定电压限制方面应发挥关键作用。然而，IAs失活的电压依赖性和恢复动力学预测，其有效性将随着去极化发作之前超极化的水平和持续时间呈指数变化。因此，长时间的超极化应会增加IAs的可用性并抑制随后的去极化；而短暂的超极化时期不应充分去除IAs的失活，从而降低其限制随后去极化反应的能力。
