Shin D S, Samoilova M, Cotic M, Zhang L, Brotchie J M, Carlen P L
Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Division of Fundamental Neurobiology, 399 Bathurst Street, MCL 12-413, Toronto, ON, Canada M5T 2S8.
Neuroscience. 2007 Oct 12;149(1):68-86. doi: 10.1016/j.neuroscience.2007.06.055. Epub 2007 Jul 28.
High frequency stimulation (HFS) is applied to many brain regions to treat a variety of neurological disorders/diseases, yet the mechanism(s) underlying its effects remains unclear. While some studies showed that HFS inhibits the stimulated nucleus, others report excitation. In this in vitro study, we stimulated the rat globus pallidus interna (entopeduncular nucleus, EP), a commonly stimulated area for Parkinson's disease, to investigate the effect of HFS-induced elevation of extracellular potassium (K(+)(e)) on rat EP neuronal activity. Whole-cell patch-clamp recordings and K(+) measurements were obtained in rat EP brain slices before, during and after HFS. After HFS (150 Hz, 10 s), K(+) increased from 2.5-9.6+/-1.4 mM, the resting membrane potential of EP neurons depolarized by 11.1+/-2.5 mV, spiking activity was significantly depressed, and input resistance decreased by 25+/-6%. The GABA(A) receptor blocker, gabazine, did not prevent these effects. The bath perfusion of 6 or 10 mM K(+), with or without synaptic blockers, mimicked the HFS-mediated effects: inhibition of spike activity, a 20+/-9% decrease in input resistance and a 17.4+/-3.0 mV depolarization. This depolarization exceeded predicted values of elevated K(+) on the resting membrane potential. A depolarization block did not fully account for the K(+)-induced inhibition of EP neuronal activity. Taken together, our results show that HFS-induced elevation of K(+) decreased EP neuronal activity by the activation of an ion conductance resulting in membrane depolarization, independent of synaptic involvement. These findings could explain the inhibitory effects of HFS on neurons of the stimulated nucleus.
高频刺激（HFS）被应用于许多脑区以治疗各种神经障碍/疾病，但其作用的潜在机制仍不清楚。虽然一些研究表明HFS抑制被刺激的核团，但其他研究报告的却是兴奋作用。在这项体外研究中，我们刺激大鼠内侧苍白球（内脚核，EP），这是帕金森病中常用的刺激区域，以研究HFS诱导的细胞外钾（K(+)(e)）升高对大鼠EP神经元活动的影响。在HFS之前、期间和之后，在大鼠EP脑片中进行全细胞膜片钳记录和K(+)测量。HFS（150 Hz，10 s）后，K(+)从2.5 - 9.6±1.4 mM增加，EP神经元的静息膜电位去极化11.1±2.5 mV，动作电位发放活动显著受到抑制，输入电阻降低25±6%。GABA(A)受体阻滞剂gabazine不能阻止这些效应。用6或10 mM K(+)进行浴灌流，无论有无突触阻滞剂，都模拟了HFS介导的效应：抑制动作电位发放活动、输入电阻降低20±9%和去极化17.4±3.0 mV。这种去极化超过了根据升高的K(+)对静息膜电位的预测值。去极化阻滞并不能完全解释K(+)诱导的EP神经元活动抑制。综上所述，我们的结果表明，HFS诱导的K(+)升高通过激活一种离子电导导致膜去极化，从而降低了EP神经元活动，且与突触无关。这些发现可以解释HFS对被刺激核团神经元的抑制作用。
