Synaptic plasticity in rat subthalamic nucleus induced by high‐frequency stimulation

Abstract

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS

“…The findings of this study motivate the investigation of phase and frequency entrainment fidelity over longer durations of stimulation coupled with quantitative measures of behavioral therapy, which will facilitate testing the potential emergence of long-term potentiation and depression that may require longer stimulus periods than used in this study (Shen et al 2003). Additionally, the number of entrained cells reported in this study was maintained at a conservative level (that is, the thresholds for phase-locked activity were high) to study phase and frequency entrainment in only those cells with the strongest entrainment.…”

“…DBS is also known to induce synaptic plasticity, even on short time scales of stimulation. In brain slices, it was shown that STN DBS could induce short-and long-term potentiation as well as long-term depression (Shen et al 2003). Although presynaptic long-term depression could also be responsible for slower buildup of poststimulus responses together with vesicle depletion, the phase shift in phase-locked spike activity was previously reported to be short term and able to recover during roughly 40-s intervals between stimulation blocks (McCairn and Turner 2009), suggesting that this form of phase shift, observed in our study as well, may be short lived and thus more likely related to neurotransmitter depletion or axonal conduction delays.…”

Transcranial Current Brain Stimulation (tCS): Models and Technologies

“…The ability or inability of activation and inactivation of AMPA and NMDA receptors during electrical stimulation, and the level of ionic concentrations such as Mg and Ca in intra-or extra-cellular mediums, may change LTP/LTD responses. It has been shown that a tetanic stimulation may induce both LTP and LTD plasticity responses on different subthalamic nucleus cells [114] or in different external Mg concentrations [115]. In another study it is shown that three trains of pulses (3 s duration at 100 Hz, 20 s intervals) may induce LTD response, while if the frequency of pulses is reduced to 10 or 1 Hz, LTD is not observed, because not enough calcium ions are accumulated in postsynaptic neuron [116].…”

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…Cessation of abnormal synchronization may be an immediate effect of DBS, but anatomical reorganization (e.g., synaptic plasticity) is likely to be a much slower process. Shen et al 114 demonstrated in a brain slice preparation that HFS in the rat STN produced three types of synaptic plasticity at glutamatergic synapses. 114 The three types were 1) short-term potentiation (ϳ5 min) of the evoked postsynaptic current (EPSC), which may indicate increased glutamate release from presynaptic terminals; 2) long-term potentiation (Ͼ30 min) of the EPSC associated with probable changes in postsynaptic protein expression; and 3) long-term depression (Ͼ30 min) of the EPSC, which may signify modification of presynaptic regulation.…”