Oligodendrocyte Precursor Cells Are Accurate Sensors of Local K⁺in Mature Gray Matter

Abstract

Oligodendrocyte precursor cells (OPCs) are the major source of myelinating oligodendrocytes during development. These progenitors are highly abundant at birth and persist in the adult where they are distributed throughout the brain. The large abundance of OPCs after completion of myelination challenges their unique role as progenitors in the healthy adult brain. Here we show that adult OPCs of the barrel cortex sense fine extracellular K ϩ increases generated by neuronal activity, a property commonly assigned to differentiated astrocytes rather than to progenitors. Biophysical, pharmacological, and single-cell RT-PCR analyses demonstrate that this ability of OPCs establishes itself progressively through the postnatal upregulation of Kir4.1 K ϩ channels. In animals with advanced cortical myelination, extracellular stimulation of layer V axons induces slow K ϩ currents in OPCs, which amplitude correlates with presynaptic action potential rate. Moreover, using paired recordings, we demonstrate that the discharge of a single neuron can be detected by nearby adult OPCs, indicating that these cells are strategically located to detect local changes in extracellular K ϩ concentration during physiological neuronal activity. These results identify a novel unitary neuron-OPC connection, which transmission does not rely on neurotransmitter release and appears late in development. Beyond their abundance in the mature brain, the postnatal emergence of a physiological response of OPCs to neuronal network activity supports the view that in the adult these cells are not progenitors only.

Electrophysiological properties of NG2 + cells: Matching physiological studies with gene expression profiles

“…NG2 + cells in acute brain slices isolated from juvenile animals typically have a capacitance of 15-30 pF, a membrane resistance of 100-500 MΩ, and a stable resting membrane potential (RMP) between −80 and −100 mV (Clarke et al, 2012; De Biase et al, 2010; Haberlandt et al, 2011; Kukley et al, 2008; Lin and Bergles, 2002; Maldonado et al, 2013). This RMP is near the calculated equilibrium potential for K + (E K ), suggesting that K + channels account for the majority of the resting membrane conductance.…”

“…A major road-block is the lack of good pharmacological tools to specifically target these channels (Feliciangeli et al, 2014). In a recent study, no change in NG2 + cell current properties was found in a TWIK1 knockout mouse, and no effect was observed on applying isoflurane, an activator of TREK1 (Maldonado et al, 2013). Yet, the RNA-Seq transcriptome database has identified several K 2P isoforms, notably TWIK1 ( Kcnk1 ), TREK1 ( Kcnk2 ), and Kcnk10 , as highly-expressed in NG2 + cells (See Table 1) (Zhang et al, 2014).…”

“…It has been shown that NG2 + cells undergo a dramatic change in their current-voltage relationship over the course of development from the first to the fifth postnatal week, transitioning from outward rectification to an increasingly linear phenotype (De Biase et al, 2010; Maldonado et al, 2013). This change has been attributed to an increase in Kir4.1 expression, as the Ba 2+ -sensitivity of the currents increases over the same time period (Maldonado et al, 2013).…”

Changes in the proliferative capacity of NG2 cell subpopulations during postnatal development of the mouse hippocampus

“…These channels detect local changes of extracellular K ? during neuronal activity and are composed of the Kir4.1 subunit (Djukic et al 2007;Maldonado et al 2013;Schröder et al 2002). The variable expression of Kir currents in juvenile hippocampus might be due to different developmental stages of the NG2 glia because during maturation current densities increased and became more homogeneous.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…Further, the expression of high levels of "leak" potassium channels and the connection with neurons through conventional synapses make NG2 glia able to sense even small changes in neuronal activity with an extremely high temporal and spatial resolution. Of note, NG2 glia have been reported to detect fine changes of extracellular potassium concentration due to the discharge of a single neuron via the inward-rectifier Kir4.1 potassium channels [78,80]. Similarly, by employing two-photon-based glutamate uncaging to produce very localized and brief release of glutamate onto NG2 glia processes segments, Sun et al [81] showed that small neurotransmitter release events at neuron-to-NG2 cell synapses can be sensed via the generation of local depolarizations and, consequentially, local Ca 2+ signals in NG2 glia processes.…”