Calcium Signaling in Schwann cells

Abstract

In addition to providing structural, metabolic and trophic support to neurons, glial cells of the central, peripheral and enteric nervous systems (CNS, PNS, ENS) respond to and regulate neural activity. One of the most well characterized features of this response is an increase of intracellular calcium. Astrocytes at synapses of the CNS, oligodendrocytes along axons of the CNS, enteric glia associated with the cell bodies and axonal varicosities of the ENS, and Schwann cells at the neuromuscular junction (NMJ) and along peripheral nerves of the PNS, all exhibit this response. Recent technical advances have facilitated the imaging of neural activity-dependent calcium responses in large populations of glial cells and thus provided a new tool to evaluate the physiological significance of these responses. This mini-review summarizes the mechanisms and functional role of activity-induced calcium signaling within Schwann cells, including terminal/perisynaptic Schwann cells (TPSCs) at the NMJ and axonal Schwann cells (ASCs) within peripheral nerves.

Keywords: Schwann; activity; calcium; glia; neuromuscular.

Figure 1.

Activity-induced Ca²⁺ responses in TPSCs of the early postnatal diaphragm. Postnatal day 7 (P7) diaphragm muscle of Wnt1-Cre; conditional GCaMP3 mice was imaged before (Pre-stim) and after (40s, 45s Nerve Stim) phrenic nerve stimulation in the presence of the myosin inhibitor BHC to block movement. Top right and bottom left panels are low and high power spatial maps of fluorescence intensity of TPSCs generated in response to nerve stimulation. Bottom right panel depicts regions of interest, representing individual TPSCs, selected for analysis. Adapted from Heredia et al., 2018a.

Figure 2.

Activity-induced Ca²⁺ _responses in TPSCs of the adult diaphragm. Diaphragm muscle of P80 Sox10-Cre, conditional GCaMP6f mice was imaged in response to high-frequency nerve stimulation (40 Hz, 45s) of the phrenic nerve in the presence of the myosin inhibitor BHC to block movement. Left two images (A,B) and middle two images (C,D) are spatial maps of fluorescence intensity and regions of interest generated in response to stimulation in the absence or presence of the P2Y₁R antagonist MRS2500; far-right image (E) is α-BTX-labeled nicotinic AChR clusters simultaneously imaged with a Gemini Splitter according to Heredia et al., 2018c.

Figure 3.

Activity-induced Ca²⁺ responses in the membrane of TPSCs are mediated by P2Y₁R. Diaphragm muscle of P7 Sox10-Cre; conditional LCK-GCaMP6f (membrane-targeted GCaMP6f) mice was imaged in response to high-frequency stimulation (40 Hz, 45s) of the phrenic nerve in the presence of the myosin inhibitor BHC to block movement. A and B are spatial maps of fluorescence intensity generated in response to stimulation in the absence or presence of the P2Y₁R antagonist MRS2500, respectively. Bottom graph is a comparison of background-subtracted fluorescence responses. Arrow indicates onset of nerve stimulation.

Figure 4.

Summary of the mechanisms and effects of activity-induced Ca²⁺ signaling in TPSCs at the NMJ and ASCs along peripheral nerves. A, At the NMJ between motor nerve terminal (green) and motor endplate of skeletal muscle fiber (orange), the TPSC (yellow) contains purinergic P2Y₁ and muscarinic receptors that transduce ATP and ACh released by active motor neurons. These receptors result in the production of the second messenger IP₃, which triggers the release of Ca²⁺ from the endoplasmic reticulum (ER; blue semicircle) to regulate synaptic plasticity, synapse elimination and muscle fatigue. B, Along peripheral sensory and motor axons, ATP released from active axons through pannexins or volume-activated channels (purple) stimulate purinergic P2Y₂ receptors, which triggers IP₃-mediated release of Ca²⁺ from ER into the cytosol and into the mitochondria via the mitochondrial uniporter (pink). This purinergic pathway downregulates ASC proliferation and upregulates ASC myelination of peripheral axons. A second nerve-derived signal of unknown origin (??) stimulates the influx of extracellular Ca²⁺ into ASCs via unknown Ca²⁺ or non-selective cation channels (orange bars).