APs are generated by activation of specific voltage–gated Na⁺ (Na_V) and K⁺ (K_V) channels, and propagate autoregeneratively along axons. In non-myelinated fibers APs travel successively through ion channels expressed all along the axons (Figure 1A1) (Debanne et al., 2011). In myelinated fibers, ion channels are mainly clustered in nodal (Na_V1.6, K_V7.2-3) and juxtaparanodal (JPN, K_V1.1-2) regions, and conduction is saltatory (Figures 1A2,A3) (Debanne et al., 2011; Buttermore et al., 2013). Ion flows generate local currents in the periaxonal space, which can influence surrounding cells via ephaptic coupling (Debanne et al., 2011).

Firing axons also release neurotransmitters (Figure 1B). Electrical or chemical stimulation in vitro induces extrasynaptic axonal ATP secretion through volume-activated anion channels (VAACs), via vesicular pathways (Verderio et al., 2006; Fields and Ni, 2010). Electrical stimulation (ES) evokes vesicular release of glutamate (Glu) along DRG axons, at least in cocultures with oligodendrocytes (Wake et al., 2011). Observations demonstrating exocytosis of large dense core vesicles by chemically depolarized axons of trigeminal ganglion neurons further support the concept of activity-induced extrasynaptic axonal secretion (Sobota et al., 2010).

In addition, axons are physically coupled to SCs via adhesive junctions, such as the paranodal junctions (PNJs) (Figure 1C) (Buttermore et al., 2013). The expression of specific axonal adhesion molecules is under regulation by ES in a pattern-specific manner (Itoh et al., 1997).

SC responses to neuronal activity were initially recorded on the squid giant axon by electrophysiology (Evans et al., 1991). ES of axons or perfusion of neurotransmitters induced SC membrane hyperpolarization (Evans et al., 1991). Similar responses have been also reported in vertebrates, mainly in the form of SC Ca²⁺ transients that develop subsequently to ES of myelinated and unmyelinated fibers (Figures 1D1,D2) (Brunet and Jirounek, 1994; Lev-Ram and Ellisman, 1995; Mayer et al., 1999).

mSCs and nmSCs express molecules, which allow them to respond to electrical or chemical axonal stimuli (Figure 1). SC “activity sensors,” including voltage- and ligand-gated ion channels, transporters, pumps, G-protein coupled receptors (GPCRs), connexins (Cx) of hemichannels and GJs, have been detected at mRNA and protein levels in vivo (animal tissues or human biopsies), ex vivo (nerve preparations) and/or in vitro (SC cultures), using biochemical and functional approaches (Dememes et al., 1995; Dezawa et al., 1998; Mayer et al., 1998; Verkhratsky and Steinhauser, 2000; Altevogt et al., 2002; Baker, 2002; Fields and Burnstock, 2006; Loreti et al., 2006; Magnaghi et al., 2006; Saitoh and Araki, 2010; Procacci et al., 2012; Nualart-Marti et al., 2013). A summary of the so far-identified SC receptors and ion channels is presented in Table 1.

Responsiveness of SCs to neuronal activity is developmentally regulated. Downregulation of K_V channel expression during early myelination, and clustering to microvilli in mature mSCs is a characteristic example (Figure 1) (Wilson and Chiu, 1990). However, scarce evidence exists regarding the developmental regulation of other SC activity sensors. To gain further insight, we analyzed microarray data previously published by our group (Verdier et al., 2012), on wild type (WT) mouse sciatic nerve (SN) at different developmental stages. Since the analyzed samples are highly enriched in SCs, we expect that the majority of the detected sensors represent SC molecules and do not derive from axon specific transcripts (Willis et al., 2007; Gumy et al., 2011), (see also Table 1). Our results -summarized in Table 1- corroborate and complete existing data, confirming the expression of specific voltage- (e.g., Na_V, K_V, voltage-gated Ca²⁺ channels; Ca_V, Cl_V), and ligand-gated (e.g., purinergic P2X and ionotropic glutamate receptors -iGluRs) ion channels, and of GPCRs (e.g., purinergic P2Y, muscarinic acetylcholine receptors, GABA_B receptors) (Fink et al., 1999; Baker, 2002; Loreti et al., 2006; Magnaghi et al., 2006). In addition, they reveal previously non-described mammalian SC expression of nicotinic acetylcholine receptors and TRP channels. Apart from the known regulation of K⁺ channels, our data suggest that expression of Na⁺, Ca²⁺, Cl⁻, and TRP channels, purinergic receptors and iGluRs is also significantly regulated during development.

These transcriptional modulations could result as adaptations of SCs to different neuronal firing modes. The reduction and restriction of K_V channels in mSC microvilli most likely corresponds to the need for K⁺ buffering mainly in nodal regions (see also paragraph “K⁺ uptake by SCs”) (Wilson and Chiu, 1990; Baker, 2002). In addition, nmSC inwardly rectifying K⁺ (Kir)-currents and T-type Ca_V depend on axonal firing (Konishi, 1994; Beaudu-Lange et al., 2000). Given that the firing patterns of nerve fibers change during maturation (Fitzgerald, 1987), we speculate that developmental regulation of SC activity sensors could be a direct glial response to axonal activity alterations. Alternatively, it may reflect mere phenotypic changes during SC maturation.

Further SC responses to neuronal activity will be the focus of the following paragraphs.

Neuronal activity depends on the maintenance of axonal integrity and energetic status. Both nmSCs and mSCs provide neurotropic and metabolic support to adjacent neurons (Griffin and Thompson, 2008; Nave, 2010). This support is under the control of axonal activity. In response to ES and ATP, cultured SCs secrete nerve growth factor (NGF) and brain-derived neurotropic factor (BDNF), respectively, promoting axonal growth (Figure 1H) (Verderio et al., 2006; Huang et al., 2010). In addition, chemical depolarization triggers vesicular transport of molecules from SCs to axons (Figure 1I) at least in invertebrates (Eyman et al., 2007). Reported molecular cargo of SC-to-axon transported vesicles includes ribosome-bound mRNA, cytoskeletal components and heat-shock proteins (Court et al., 2008; Cocucci et al., 2009; Lopez-Verrilli and Court, 2012). Their exact contributions to axonal function under physiological conditions are still unknown.

Although information regarding glia-to-axon metabolic support in the PNS is scarce, inferences could be made from CNS data. Neuronal activity triggers exosome transfer of metabolic enzymes from oligodendrocytes to neurons (Fruhbeis et al., 2013), as well as release of lactate from astrocytes and uptake by neurons (Barros, 2013). Similar energy transfer processes may occur in the PNS. ES in SN increases O₂ uptake and glucose consumption, and SCs seem to be the main metabolic SN niche (Heller and Hesse, 1961). Moreover, in vivo genetic disruption of mitochondria energy production in otherwise functional mouse SCs severely impairs the structure and function of peripheral fibers (Viader et al., 2011; Funfschilling et al., 2012), suggesting that there may be SC-to-neuron energy transfer also in the PNS. However, its characterization, and potential regulation by neuronal activity await further investigation.

Peripheral neuropathies have been linked to dysregulation of SC activity sensors. Overexpression of P2X7 receptors may have a causative role in CMT1A patient demyelination due to Ca²⁺ overload (Nobbio et al., 2009). Moreover, P2X7 activation induces BDNF secretion and activates K⁺ and Cl⁻ conductances, through Big K⁺ channels and more likely via the cystic fibrosis transmembrane conductance regulator CFTR (Colomar and Amedee, 2001; Verderio et al., 2006). Interestingly, Cl⁻ imbalance leads to axonal loss with primary or secondary dysmyelination in patients and animal models with dysfunctional CFTR or the K⁺-Cl⁻ cotransporter KCC3 (Sun et al., 2010; Reznikov et al., 2013). Certain CMTX patients carry mutations in Cx32, which may lead to increased currents through the Cx32-hemichannel and to subsequent nerve damage (Abrams et al., 2002; Nualart-Marti et al., 2013). Dysregulation of SC sensors (e.g., upregulation of K_V and Na_V channels) also occurs after injury (Chiu, 1988).

To further investigate the contribution of SC activity sensor regulation to PNS dysfunctions, we checked for respective transcriptional modulations in our previously published microarray data on SN endoneuria from three mouse models of peripheral neuropathy: the Scap and Lpin1 conditional knockouts (KOs), which have defective lipid biosynthesis and exhibit PNS hypomyelination and progressive demyelination, respectively, and the Pmp22 total KO, which lacks the myelin protein PMP22 and is a model of Hereditary Neuropathy with Liability to Pressure Palsy (Table 1) (Adlkofer et al., 1995; Nadra et al., 2008; Verheijen et al., 2009; Verdier et al., 2012). With the exception of TRP channels and acetylcholine receptors, we are able to detect expression changes in all families of SC sensors. Their potential role in pathogenesis can be inferred from existing data. Upregulation of K⁺ channels may interfere with SC ability to buffer K⁺ ions or be associated with increased proliferation of dedifferentiated SCs (Wilson and Chiu, 1990, 1993) (Figures 1E2,G1). Upregulation of T-type Ca_V3.2 channels could trigger NGF release, in order to support underlying affected axons (Figure 1H) (Huang et al., 2010). A time-course analysis of the transcriptionally regulated genes during the progress of pathology, in conjunction with functional studies, would be necessary to delineate their potential destructive or protective roles in the development of neuropathy.

Myelin defects are a common feature of various peripheral neuropathies. Studies on animal models of demyelinating diseases (e.g., CMT1A, CMT1B, CMT1C, and CMTX) have demonstrated that myelin impairments affect neural influx conduction and axonal excitability through different mechanisms, including decreased electrical isolation of the axolemma, the exposure, redistribution or abnormal expression of voltage-gated ion channels, and the potential change from saltatory to continuous conduction (Brismar, 1981b, 1982; Rasminsky, 1982; Meiri et al., 1986; England et al., 1990, 1996; Schwarz et al., 1991; Rasband et al., 1998; Neuberg et al., 1999; Devaux and Scherer, 2005; Moldovan et al., 2011; Lee et al., 2013). Aberrant expression of nodal Na_V channels and nodal or juxtaparanodal K_V channels, has been confirmed in patients with CMT1A and CMT4C (Nodera et al., 2004; Arnaud et al., 2009). Computational simulations in combination with experimental observations correlate those demyelination-induced changes with alterations in axonal excitability and impulse propagation, leading to negative or positive clinical symptoms. Alteration in axonal domains can induce decreased excitability and even conduction failure underlying negative symptoms of peripheral neuropathies, such as muscle weakness (Brismar, 1981a,b; Cappelen-Smith et al., 2001; Nodera et al., 2004; Jani-Acsadi et al., 2008; Coggan et al., 2010; Moldovan et al., 2011). Alternatively, demyelination can lead to axonal hyperexcitability, spontaneous ectopic spiking and cross excitation of neighboring axons (by ephaptic coupling or crossed afterdischarge), leading to positive symptoms like neuropathic pain (Calvin et al., 1982; Rasminsky, 1982; Lisney and Pover, 1983; Lisney and Devor, 1987; Gillespie et al., 2000; Wallace et al., 2003; Gemignani et al., 2004; Coggan et al., 2010).

Axonal dysfunctions in pathologies and animal models with impaired SCs may also occur secondary to or without myelin abnormalities (Gabreels-Festen et al., 1992; Griffiths et al., 1998; Chen et al., 2003; Nave, 2010), indicating the implication of myelin-unrelated mechanisms. Failure of trophic or metabolic glia-to-neuron support may be one such mechanism. Glial support is particularly critical for neuropathic fibers, which have increased metabolic requirements, due to their decreased propagation efficiencies (Shrager and Rubinstein, 1990; De Waegh et al., 1992; Kirkpatrick and Brady, 1994; Moldovan et al., 2011). Glycogen stored in mSCs is utilized to provide neurons with lactate particularly during aglycemia (Brown et al., 2012). Likewise, exosome transport of metabolic enzymes from oligodendrocytes to axons is required to sustain neuronal survival and function under stress conditions (Fruhbeis et al., 2013), while vesicular transfer of ribosomes from mSCs is prominent in injured fibers, and promotes regeneration (Court et al., 2008, 2011; Lopez-Verrilli et al., 2013). Mutations affecting exosome-mediated intercellular communication have been recently described in CMT1C patients (Zhu et al., 2013). Direct transfer of SC molecules via GJs has been suggested in regenerating nerves (Figure 1J) (Dezawa et al., 1998). Apparently, under pathological conditions, SCs need to adjust their physiology in order to maintain the integrity and function of suffering axons.

To investigate whether glia-to-axon support mechanisms are affected in our Scap, Lpin1, and Pmp22 mouse models, we checked for transcriptional regulation of genes involved in cellular metabolism (excluding lipid metabolism, since its dysregulation is expected in the Scap and Lpin1 KOs) and vesicle trafficking, and for genes encoding potential SC exosome or other vesicular cargo (Lopez-Verrilli and Court, 2012; Fruhbeis et al., 2013). Results, depicted in Table S1, reveal changes in genes of all categories. Detailed analyses at both glial and neuronal levels are required to check the potential positive or negative impact of those alterations on the diseased phenotype, especially since some of the depicted transcripts are also present in axons (Willis et al., 2007; Gumy et al., 2011).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.