Università degli Studi di Roma Tor Vergata, Rome, Italy.
Exp Neurol. 2012 Jan;233(1):292-302. doi: 10.1016/j.expneurol.2011.10.018. Epub 2011 Oct 28.
High frequency stimulation of the subthalamic nucleus (HFS-STN) has been successfully introduced to treat symptoms of advanced Parkinson's disease (PD) (rigidity, tremor and akinesia). In spite of its extensive clinical practice, little is known at cellular level about the effects of a continuous train of electrical stimuli (>100 Hz) delivered in the STN. In this manuscript we examine the synaptic responses of substantia nigra pars compacta (SNpc) dopaminergic cells, upon continuous HFS-STN delivered in a rat brain slice preparation. We report that HFS-STN, delivered at frequencies resembling those used during DBS (100-130 Hz), caused synaptic responses in SNpc dopaminergic neurons, which summated progressively, until they reached a plateau within few tens of ms. However, if the HFS was maintained, a rapid fading of the synaptic response was observed, with an almost complete loss after 10s. Accordingly, the postsynaptic excitability, evaluated by the tonic firing rate of the SNpc dopaminergic neurons, remained unaltered during a continuous HFS-STN. Upon HFS termination, there was a rapid recovery of synaptic function. Neither a converging synaptic input, evoked by intranigral stimulation, nor the depolarizing responses to locally-applied AMPA, were affected during HFS. The loss of synaptic response by continuous HFS-STN was not prevented by inhibition of AMPA receptor desensitization, nor by antagonists of a variety of neurotransmitter receptors, known to depress synaptic transmission in the SNpc. We conclude that a HFS in the STN, with patterns resembling in vivo DBS, induces a rapid and input-specific suppression of the synaptic transmission from STN to SNpc dopaminergic neurons, that is maintained during an ongoing stimulation. The deficit of transmission between the STN and the SNpc could have a role in the therapeutic effects of the DBS procedure.
高频刺激丘脑底核（HFS-STN）已成功用于治疗晚期帕金森病（PD）的症状（僵硬、震颤和运动不能）。尽管它在临床实践中得到了广泛应用，但对于 STN 中传递的连续电刺激（>100 Hz）在细胞水平上的影响知之甚少。在本文中，我们研究了在大鼠脑切片制备中连续 HFS-STN 传递时，黑质致密部（SNpc）多巴胺能细胞的突触反应。我们报告说，HFS-STN 以类似于 DBS 期间使用的频率（100-130 Hz）传递时，会引起 SNpc 多巴胺能神经元的突触反应，这些反应逐渐累积，直到在几十毫秒内达到平台期。然而，如果维持 HFS，则会观察到突触反应迅速衰减，在 10 秒后几乎完全消失。因此，通过 SNpc 多巴胺能神经元的强直放电率评估的突触后兴奋性在连续 HFS-STN 期间保持不变。HFS 终止后，突触功能迅速恢复。在 HFS 期间，通过内黑质刺激引起的会聚突触输入以及对局部应用 AMPA 的去极化反应均不受影响。连续 HFS-STN 不会阻止 AMPA 受体脱敏的抑制或多种神经递质受体的拮抗剂防止突触反应的丧失，这些受体已知会抑制 SNpc 中的突触传递。我们得出结论，类似于体内 DBS 的模式的 STN 中的 HFS 会引起来自 STN 到 SNpc 多巴胺能神经元的突触传递的快速和输入特异性抑制，并且在持续刺激期间保持不变。STN 和 SNpc 之间的传输缺陷可能在 DBS 程序的治疗效果中起作用。
