Elsevier

Brain Stimulation

Volume 10, Issue 1, January–February 2017, Pages 51-58
Brain Stimulation

Direct Current Stimulation Modulates LTP and LTD: Activity Dependence and Dendritic Effects

https://doi.org/10.1016/j.brs.2016.10.001Get rights and content

Highlights

  • tDCS can improve learning outcomes when paired with various training paradigms, but the mechanisms for this remain unknown.

  • Here we show that DCS facilitates LTP and diminishes LTD in hippocampal slices.

  • These effects can be polarity independent, as both anodal and cathodal DCS can produce similar modulation of plasticity.

  • Outcomes depended on dendritic location and endogenous synaptic activity.

  • These results motivate an approach to tDCS protocol design that considers these factors.

Abstract

Background

Transcranial direct current stimulation (tDCS) has been reported to improve various forms of learning in humans. Stimulation is often applied during training, producing lasting enhancements that are specific to the learned task. These learning effects are thought to be mediated by altered synaptic plasticity. However, the effects of DCS during the induction of endogenous synaptic plasticity remain largely unexplored.

Objective/Hypothesis

Here we are interested in the effects of DCS applied during synaptic plasticity induction.

Methods

To model endogenous plasticity we induced long-term potentiation (LTP) and depression (LTD) at Schaffer collateral synapses in CA1 of rat hippocampal slices. Anodal and cathodal DCS at 20 V/m were applied throughout plasticity induction in both apical and basal dendritic compartments.

Results

When DCS was paired with concurrent plasticity induction, the resulting plasticity was biased towards potentiation, such that LTP was enhanced and LTD was reduced. Remarkably, both anodal and cathodal stimulation can produce this bias, depending on the dendritic location and type of plasticity induction. Cathodal DCS enhanced LTP in apical dendrites while anodal DCS enhanced LTP in basal dendrites. Both anodal and cathodal DCS reduced LTD in apical dendrites. DCS did not affect synapses that were weakly active or when NMDA receptors were blocked.

Conclusions

These results highlight the role of DCS as a modulator, rather than inducer of synaptic plasticity, as well as the dependence of DCS effects on the spatial and temporal properties of endogenous synaptic activity. The relevance of the present results to human tDCS should be validated in future studies.

Introduction

Transcranial direct current stimulation (tDCS) applies a weak constant current of 2 mA or less across the scalp. This apparently simple technique is currently under investigation for a wide variety of conditions, including psychiatric disorders, neurorehabilitation and cognitive enhancement [1], [2], [3]. Stimulation is often paired with a training task, leading to task-specific enhancements in learning performance [1], [4]. Despite the observation of pharmacological, neuro-physiological and imaging effects in humans [5] and animals [6], a coherent picture of the relevant cellular mechanisms is yet to emerge.

Learning and memory are thought to be mediated by synaptic plasticity [7] and training paradigms in humans presumably influence learning by inducing plasticity [8]. Despite the common practice of applying tDCS during training, cellular effects of DCS applied during endogenous plasticity induction remain largely unexplored. Instead, the majority of research has analysed effects when DCS precedes plasticity induction [9], [10], [11], or is paired with endogenous activity otherwise not known to induce plasticity [12], [13], [14]. Here we are interested in the effects of DCS applied during training, i.e. concurrent with synaptic plasticity induction. As a model of endogenous synaptic plasticity, we induced long-term potentiation (LTP) and depression (LTD) using canonical protocols (pulse trains delivered to Schaffer collateral synapses in CA1 of rat hippocampal slices). By sweeping across induction frequencies we capture a frequency–response function (FRF), which has been widely used to study the predictions of the Bienenstock, Cooper and Munro (BCM) theory of synaptic plasticity. Here we show that DCS can shift the FRF, facilitating LTP and diminishing LTD, similar to BCM-like metaplasticity [15].

A prevailing mechanistic explanation is that tDCS produces shifts in cortical excitability, with anodal stimulation increasing excitability and cathodal stimulation decreasing excitability [5]. This excitability hypothesis is rooted in physiological evidence that DCS modulates membrane potential at neuronal somas, leading to changes in firing rate and timing [16], [17], [18], [19], [20]. Based on these observations, anodal and cathodal tDCS are often assumed to produce LTP and LTD-like effects, respectively, for an entire brain region [21], [22], [23], [24]. However, this reasoning ignores the gradient of membrane polarization induced in any neuron during DCS and the role of endogenous synaptic activity in determining effects.

Here we show that DCS effects vary greatly within a small population of neurons, depending on dendritic location and endogenous synaptic activity. Both anodal and cathodal DCS facilitated LTP, but in different dendritic compartments. Moreover, when paired with LTD, DCS effects were independent of polarity. Both anodal and cathodal DCS reduced LTD in the same dendritic compartment. Finally, we show that DCS did not induce plasticity, but rather acted only as a modulator of endogenous synaptic plasticity. Our results motivate a more nuanced approach, which accounts for the properties of endogenous synaptic activity in predicting DCS effects.

Section snippets

Materials and methods

All animal experiments were carried out in accordance with guidelines and protocols approved by the Institutional Animal Care and Use Committee (IACUC) at The City College of New York, CUNY (Protocol No: 846.3).

Hippocampal brain slices were prepared from male Wistar rats aged 3–5 weeks old, which were deeply anaesthetized with ketamine (7.4 mg kg−1) and xylazine (0.7 mg kg−1) applied I.P., and killed by cervical dislocation. The brain was quickly removed and immersed in chilled (2–6 °C)

DCS shifts the frequency–response function

Trains of synaptic activity have conventionally been used to induce synaptic plasticity in hippocampal slices [25], [29]. As a model of endogenous synaptic plasticity, trains of 900 pulses at varying frequencies (0.5, 1, 5, 20 Hz) were applied to the Schaffer collateral pathway synapsing on CA1 apical dendrites. Low frequency stimulation (LFS) generated LTD (0.5 Hz: 84.1 ± 2.7%, p < 0.001, n = 10; 1 Hz: 78.9 ± 2.9%, p < 0.0001, n = 9), while high frequency stimulation (HFS) generated LTP

LTP, LTD, and learning

There is now strong evidence for a role of both LTP and LTD-like processes in various types of learning and memory [36], [37], [38], [39], [40], [41]. At the behavioural level, learning is likely to involve both of these processes, with the precise degree of each depending on the specific behaviour. For example, some learned behaviours directly require habituation to a familiar stimulus and are specifically dependent on LTD [42], [43]. Other learned behaviours involve formation of new

Acknowledgments

This work is supported by NIH grant R01MH092926.

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