L-Type Ca2+ Channels of NG2 Glia Determine Proliferation and NMDA Receptor-Dependent Plasticity.

Na Zhao,Bogdan Cãtãlin,Frank Kirchhoff,Wenhui Huang,Anja Scheller

doi:10.3389/fcell.2021.759477

Abstract

NG2 (nerve/glial antigen 2) glia are uniformly distributed in the gray and white matter of the central nervous system (CNS). They are the major proliferating cells in the brain and can differentiate into oligodendrocytes. NG2 glia do not only receive synaptic input from excitatory and inhibitory neurons, but also secrete growth factors and cytokines, modulating CNS homeostasis. They express several receptors and ion channels that play a role in rapidly responding upon synaptic signals and generating fast feedback, potentially regulating their own properties. Ca2+ influx via voltage-gated Ca2+ channels (VGCCs) induces an intracellular Ca2+ rise initiating a series of cellular activities. We confirmed that NG2 glia express L-type VGCCs in the white and gray matter during CNS development, particularly in the early postnatal stage. However, the function of L-type VGCCs in NG2 glia remains elusive. Therefore, we deleted L-type VGCC subtypes Cav1.2 and Cav1.3 genes conditionally in NG2 glia by crossbreeding NG2-CreERT2 knock-in mice to floxed Cav1.2 and flexed Cav1.3 transgenic mice. Our results showed that ablation of Cav1.2 and Cav1.3 strongly inhibited the proliferation of cortical NG2 glia, while differentiation in white and gray matter was not affected. As a consequence, no difference on myelination could be detected in various brain regions. In addition, we observed morphological alterations of the nodes of Ranvier induced by VGCC-deficient NG2 glia, i.e., shortened paired paranodes in the corpus callosum. Furthermore, deletion of Cav1.2 and Cav1.3 largely eliminated N-methyl-D-aspartate (NMDA)-dependent long-term depression (LTD) and potentiation in the hippocampus while the synaptic input to NG2 glia from axons remained unaltered. We conclude that L-type VGCCs of NG2 glia are essential for cell proliferation and proper structural organization of nodes of Ranvier, but not for differentiation and myelin compaction. In addition, L-type VGCCs of NG2 glia contribute to the regulation of long-term neuronal plasticity.

Highlights

NG2 glia constitute about 5–8% of brain cells
To study the expression of L-type voltage-gated Ca2+ channels (VGCCs) in NG2 glia in different brain regions during central nervous system (CNS) development, we analyzed reporter+ NG2 glia in the white matter
Ca2+ elevations of NG2 glia in the somatosensory cortex were evoked by successive depolarization to 10 mV in control (G) and double knockout (dKO) mice (H)

Summary

Introduction

NG2 glia constitute about 5–8% of brain cells They are uniformly distributed in the gray and white matter of the central nervous system (CNS) and act as oligodendrocyte precursor cells (OPC) (Nishiyama et al, 2009). In the adult CNS, NG2 glia are the major proliferating cell population outside neurogenic regions (e.g., subventricular zone and hippocampus). The proliferation rate of NG2 glia is faster in white than in gray matter with the shortest cell cycle in the corpus callosum (2.7 days), compared to spinal cord (4.4 days), and optic nerve (7.6 days), and almost 3 weeks (18.6 days) in the cortex (Zonouzi et al, 2011; Young et al, 2013)

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