Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl- channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability

Recent Insights into the Functional Role of AMPA Receptors in the Oligodendrocyte Lineage Cells In Vivo

This review discusses the experimental findings of several recent studies which investigated the functional role of AMPA receptors (AMPARs) in oligodendrocyte lineage cells in vivo, in mice and in zebrafish. These studies provided valuable information showing that oligodendroglial AMPARs may be involved in the modulation of proliferation, differentiation, and migration of oligodendroglial progenitors, as well as survival of myelinating oligodendrocytes during physiological conditions in vivo. They also suggested that targeting the subunit composition of AMPARs may be an important strategy for treating diseases. However, at the same time, the experimental findings taken together still do not provide a clear picture on the topic. Hence, new ideas and new experimental designs are required for understanding the functional role of AMPARs in the oligodendrocyte lineage cells in vivo. It is also necessary to consider more closely the temporal and spatial aspects of AMPAR-mediated signalling in the oligodendrocyte lineage cells. These two important aspects are routinely discussed by neuronal physiologists studying glutamatergic synaptic transmission, but are rarely debated and thought about by researchers studying glial cells

Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum

<div><p>In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells.</p></div

The rate and the time course of delayed glutamate release at axon-oligodendrocyte precursor cell (OPC) synapses depend on the stimulation paradigm.

<p><b>(A)</b> Average peak rate of the delayed events after the stimulation with 2 pulses (<i>n</i> = 6 cells), 5 pulses (<i>n</i> = 6 cells), or 20 pulses (<i>n</i> = 8 cells) at 25 Hz. The box “Spont.” shows the frequency of the spontaneous events recorded before each stimulation train. One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). <b>(B)</b> Average rate of delayed events after the stimulation with 2, 5, or 25 pulses at 25 Hz. Solid lines indicate monoexponential fits to the events rate. The same cells used as in <b>(A)</b>. <b>(C)</b> Average decay time constants of the delayed events rate after the stimulation with 2, 5, or 20 pulses at 25 Hz. The same cells used as in <b>(A).</b> One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). <b>(D)</b> Data and statistical comparisons are as in <b>(A)</b> but for the stimulation paradigms of 5 pulses at 5 Hz (<i>n</i> = 7 cells), 25 Hz (<i>n</i> = 7 cells), and 100 Hz (<i>n</i> = 6 cells). One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). <b>(E)</b> Data as in <b>(B)</b> but for the stimulation paradigms of 5 pulses at 5, 25, and 100 Hz. The same cells used as in <b>(D)</b>. <b>(F)</b> Data and statistical comparisons are as in <b>(C)</b> but for the stimulation paradigms of 5 pulses at 5, 25, and 100 Hz. The same cells used as in <b>(D)</b>. One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). <b>(G)</b> Data and statistical comparisons are as in <b>(A)</b> but for the stimulation paradigms of 20 pulses at 25 Hz (<i>n</i> = 8 cells) and 100 Hz (<i>n</i> = 13 cells). One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). <b>(H)</b> Data as in <b>(B)</b> but for the stimulation paradigms of 20 pulses at 25 and 100 Hz. The same cells used as in <b>(G)</b>. <b>(I)</b> Data and statistical comparisons are as in <b>(C)</b> but for the stimulation paradigms of 20 pulses at 25 and 100 Hz. The same cells used as in <b>(G)</b>. One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s019" target="_blank">S7 Data</a>). Box and whisker plots: the bottom and top of each box represent 25th and 75th percentiles of the data, respectively, while whiskers represent 10th and 90th percentiles. The midline represents the median. The numerical data used in A, C, D, F, G, and I are included in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s020" target="_blank">S8 Data</a>.</p

Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy.

The hyperpolarization-activated cation current I(h) is an important regulator of neuronal excitability and may contribute to the properties of the dentate gyrus granule (DGG) cells, which constitute the input site of the canonical hippocampal circuit. Here, we investigated changes in I(h) in DGG cells in human temporal lobe epilepsy (TLE) and the rat pilocarpine model of TLE using the patch-clamp technique. Messenger-RNA (mRNA) expression of I(h)-conducting HCN1, 2 and 4 isoforms was determined using semi-quantitative in-situ hybridization. I(h) density was ∼1.8-fold greater in DGG cells of TLE patients with Ammon's horn sclerosis (AHS) as compared to patients without AHS. The magnitude of somatodendritic I(h) was enhanced also in DGG cells in epileptic rats, most robustly during the latent phase after status epilepticus and prior to the occurrence of spontaneous epileptic seizures. During the chronic phase, I(h) was increased ∼1.7-fold. This increase of I(h) was paralleled by an increase in HCN1 and HCN4 mRNA expression, whereas HCN2 expression was unchanged. Our data demonstrate an epilepsy-associated upregulation of I(h) likely due to increased HCN1 and HCN4 expression, which indicate plasticity of I(h) during epileptogenesis and which may contribute to a compensatory decrease in neuronal excitability of DGG cells

The time course and the amount of synaptic charge transfer through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at axon–oligodendrocyte precursor cell (OPC) synapses depend on the stimulation paradigm.

<p><b>(A)</b> Average synaptic charge transfer upon stimulation of callosal axons with trains of four different frequencies and durations plotted versus real time. Each color (blue, red, dark red, or black) represents mean charge transfer from <i>n</i> = 5 cells (5 pulses at 5 Hz), <i>n</i> = 5 cells (5 pulses at 25 Hz), <i>n</i> = 5 cells (20 pulses at 25 Hz), and <i>n</i> = 10 cells (20 pulses at 100 Hz). Charge transfer is shown in 5-ms bins. Note that plotting charge transfer versus real time allows observing not only the amount of synaptic facilitation but also its distribution over time, and it differs dramatically depending on the stimulation paradigm (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.g003" target="_blank">Fig 3A & 3D</a>). <b>(B)</b> Total average synaptic charge transfer during the stimulation trains of different frequencies and durations. Both phasic and asynchronous charge transfer during the trains are considered for these bar graphs. The same cells used as in <b>(A)</b>. One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s021" target="_blank">S9 Data</a>). <b>(C)</b> Total synaptic charge transferred by the delayed currents occurring after the stimulation trains of different frequencies and durations. The same cells used as in <b>(A)</b>. One-way ANOVA (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s021" target="_blank">S9 Data</a>). <b>(D)</b> Percentage contribution of synaptic charge transferred during (phasic + asynchronous charge) and after (delayed charge) the stimulation trains of different frequencies and durations. White numbers on the bars indicate the proportion of charge transferred during the train. Box and whisker plots: the bottom and top of each box represent 25th and 75th percentiles of the data, respectively, while whiskers represent 10th and 90th percentiles. The midline represents the median. The numerical data used in B–C are included in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s022" target="_blank">S10 Data</a>.</p

Transient stimulation of callosal axons in vivo at 5 Hz but not at 25 Hz or 300 Hz promotes differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes (OLs).

<p><b>(A)</b> Scheme describing experimental design for studying effects of callosal stimulation in vivo on proliferation and differentiation of OPCs. <b>(B)</b> Scheme showing sagittal section of mouse brain and the position of an electrode array used for electrical stimulation of the corpus callosum. <b>(C)</b> Schematic drawings of the investigated cell types. For cell counting, OPCs were identified as NG2⁺CC1^- cells, premyelinating OLs (pre-OLs) as NG2⁺CC1⁺ cells, and myelinating OLs as NG2^- cells expressing CC1 in their soma. Within the OL lineage, 5-ethynyl-2´-deoxyuridine (EdU) only labels proliferating OPCs. However, the progeny of an EdU⁺ OPC will be EdU⁺. <b>(D)</b> Coronal sections of the corpus callosum. Maximum intensity projection (from 14 successive confocal planes) showing triple channel immunofluorescent labelling with DAPI (top left, blue), NG2 (top right, green), CC1 (bottom left, red), and the overlay of 3 channels (bottom right). White dashed line denotes the middle region of the corpus callosum used for cell counting. White arrow indicates midline of the brain. Scale bars: 100 μm. <b>(E)</b> As in <b>(D)</b>, but higher magnification example of one NG2⁺CC1^- OPC (arrow) and three NG2^-CC1⁺ OLs (arrowheads). Maximum intensity projection was generated from a z-stack of 3 successive confocal planes. Note that some processes of an NG2⁺ OPC are clearly visible. Scale bars: 10 μm. <b>(F)</b> As in <b>(E)</b>, but an example of one NG2⁺CC1⁺ pre-OL (arrow). Note that the expression level of NG2 is weaker than in OPCs, and the expression level of CC1 is weaker than in OLs (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.g007" target="_blank">Fig 7E</a>). Scale bars: 10 μm. <b>(G–I)</b> Average density of <b>(G)</b> OPCs, (<b>H)</b> pre-OLs, and (<b>I)</b> OLs in corpus callosum upon electrical stimulation of callosal axons at 5 Hz (<i>n</i> = 5 mice, total 13 slices), 25 Hz (<i>n</i> = 5 mice, total 16 slices), or 300 Hz (<i>n</i> = 5 mice, total 17 slices) versus sham-stimulated controls (<i>n</i> = 7 mice, total 25 slices). Note that differentiation rate was significantly increased by 5 Hz but not by 25 Hz or 300 Hz stimulation <b>(H)</b>. Nested ANOVA and post hoc Tukey were used for statistical analysis (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s025" target="_blank">S13 Data</a>). Box and whisker plots: the bottom and top of each box represent 25th and 75th percentiles of the data, respectively, while whiskers represent 10th and 90th percentiles. The midline represents the median. The numerical data used in G–I are included in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2001993#pbio.2001993.s026" target="_blank">S14 Data</a>.</p