Leresche N, Parri H R, Erdemli G, Guyon A, Turner J P, Williams S R, Asprodini E, Crunelli V
Institut des Neurosciences, Centre National de la Recherche Scientifique, UMR 7624 Université Pierre et Marie Curie, Paris, France.
J Neurosci. 1998 Jul 1;18(13):4842-53. doi: 10.1523/JNEUROSCI.18-13-04842.1998.
The action of ethosuximide (ETX) on Na+, K+, and Ca2+ currents and on tonic and burst-firing patterns was investigated in rat and cat thalamic neurons in vitro by using patch and sharp microelectrode recordings. In thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (LGN), ETX (0.75-1 mM) decreased the noninactivating Na+ current, INaP, by 60% but had no effect on the transient Na+ current. In TC neurons of the rat and cat LGN, the whole-cell transient outward current was not affected by ETX (up to 1 mM), but the sustained outward current was decreased by 39% at 20 mV in the presence of ETX (0.25-0.5 mM): this reduction was not observed in a low Ca2+ (0.5 mM) and high Mg2+ (8 mM) medium or in the presence of Ni2+ (1 mM) and Cd2+ (100 microM). In addition, ETX (up to 1 mM) had no effect on the low-threshold Ca2+ current, IT, of TC neurons of the rat ventrobasal (VB) thalamus and LGN and in neurons of the rat nucleus reticularis thalami nor on the high-threshold Ca2+ current in TC neurons of the rat LGN. Sharp microelectrode recordings in TC neurons of the rat and cat LGN and VB showed that ETX did not change the resting membrane potential but increased the apparent input resistance at potentials greater than -60 mV, resulting in an increase in tonic firing. In contrast, ETX decreased the number of action potentials in the burst evoked by a low-threshold Ca2+ potential. The frequency of the remaining action potentials in a burst also was decreased, whereas the latency of the first action potential was increased. Similar effects were observed on the burst firing evoked during intrinsic delta oscillations. These results indicate an action of ETX on INaP and on the Ca2+-activated K+ current, which explains the decrease in burst firing and the increase in tonic firing, and, together with the lack of action on low- and high-threshold Ca2+ currents, the results cast doubts on the hypothesis that a reduction of IT in thalamic neurons underlies the therapeutic action of this anti-absence medicine.
通过膜片钳和尖锐微电极记录技术，在体外对大鼠和猫的丘脑神经元研究了乙琥胺（ETX）对钠离子、钾离子和钙离子电流以及对紧张性放电和爆发性放电模式的作用。在大鼠背外侧膝状体核（LGN）的丘脑皮质（TC）神经元中，ETX（0.75 - 1 mM）使非失活钠离子电流INaP降低了60%，但对瞬时钠离子电流没有影响。在大鼠和猫LGN的TC神经元中，全细胞瞬时外向电流不受ETX（高达1 mM）影响，但在存在ETX（0.25 - 0.5 mM）时，在20 mV下持续外向电流降低了39%：在低钙（0.5 mM）和高镁（8 mM）培养基中或存在镍离子（1 mM）和镉离子（100 microM）时未观察到这种降低。此外，ETX（高达1 mM）对大鼠腹侧基底（VB）丘脑和LGN的TC神经元以及大鼠丘脑网状核神经元的低阈值钙离子电流IT没有影响，对大鼠LGN的TC神经元的高阈值钙离子电流也没有影响。在大鼠和猫LGN及VB的TC神经元中进行的尖锐微电极记录显示，ETX没有改变静息膜电位，但在电位大于 - 60 mV时增加了表观输入电阻，导致紧张性放电增加。相反，ETX减少了由低阈值钙离子电位诱发的爆发中的动作电位数量。爆发中其余动作电位的频率也降低了，而第一个动作电位的潜伏期增加了。在内在δ振荡期间诱发的爆发性放电上也观察到了类似的效应。这些结果表明ETX对INaP和钙激活钾电流有作用，这解释了爆发性放电的减少和紧张性放电的增加，并且，由于对低阈值和高阈值钙离子电流没有作用，这些结果对丘脑神经元中IT降低是这种抗失神药物治疗作用基础的假说提出了质疑。
