Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain

Doesn't your doctor already having you use some tDCS rehab without knowing exactly how it works?

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  But did you invalidate this research?

Transcranial Brain Stimulation: No Benefit for Stroke Rehab

 

Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain

• Hiromu Monai,
• Masamichi Ohkura,
• Mika Tanaka,
• Yuki Oe,
• Ayumu Konno,
• Hirokazu Hirai,
• Katsuhiko Mikoshiba,
• Shigeyoshi Itohara,
• Junichi Nakai,
• Youichi Iwai &
• Hajime Hirase 

Nature Communications volume 7, Article number: 11100 (2016) Cite this article

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Abstract

Transcranical direct current stimulation (tDCS) is a treatment known to ameliorate various neurological conditions and enhance memory and cognition in humans. tDCS has gained traction for its potential therapeutic value; however, little is known about its mechanism of action. Using a transgenic mouse expressing G-CaMP7 in astrocytes and a subpopulation of excitatory neurons, we find that tDCS induces large-amplitude astrocytic Ca²⁺ surges across the entire cortex with no obvious changes in the local field potential. Moreover, sensory evoked cortical responses are enhanced after tDCS. These enhancements are dependent on the alpha-1 adrenergic receptor and are not observed in IP₃R2 (inositol trisphosphate receptor type 2) knockout mice, in which astrocytic Ca²⁺ surges are absent. Together, we propose that tDCS changes the metaplasticity of the cortex through astrocytic Ca²⁺/IP₃ signalling.

Introduction

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation procedure, in which weak d.c. current (typically 1 mA) is applied over cortical areas for 10–30 min through the skull. tDCS has been shown effective for alleviating neuropsychiatric and neurological conditions such as major depression in humans¹. tDCS has also been demonstrated to enhance learning and memory formation^2,3. Previous work demonstrated that tDCS applied over the motor cortex of human subjects increases the excitability of the motor cortex in a N-methyl-D-aspartate receptor (NMDAR)-dependent manner⁴. Application of d.c. over mouse motor cortical slice has demonstrated that DCS enhances synaptic response that depends on the NMDAR and brain-derived neurotrophic factor⁵. However, detailed cellular mechanisms for in vivo tDCS-induced plasticity remain largely unknown.

Multiple studies show crucial roles of astrocytes in NMDAR-dependent plasticity^6,7,8,9, using rodent in vitro and in vivo preparations. These studies imply that astrocytes make gliotransmission to secrete signalling molecules to synapses. Several lines of evidence that gliotransmission occurs by intracellular Ca²⁺ elevation have been reported, although the exact mechanism of gliotransmission is still controversial^10,11. As recent animal models of tDCS have successfully demonstrated enhancements in learning and synaptic plasticity^2,12,13, we sought to address the dynamical activity of the brain during tDCS by Ca²⁺ imaging.

G-CaMP7 is a green fluorescent protein (GFP)-based Ca²⁺ indicator protein that was improved from the original G-CaMP¹⁴ by directed site mutagenesis to yield higher signal-to-noise ratio and faster response time, making it suitable for monitoring neuronal activity¹⁵. Here we introduce a transgenic mouse line ‘G7NG817’ in which astrocytes and a subset of cortical neurons express G-CaMP7 permitting transcranial imaging, using a standard stereo fluorescence microscope. Surprisingly, we find that tDCS invokes large-amplitude and synchronized Ca²⁺ surges in astrocytes. This phenomenon lead to the hypothesis that tDCS-induced astrocytic activity affects the metaplasticity of the cortex in a similar manner to astrocytic modulation of synaptic plasticity by neuromodulators¹⁶.

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