Neuronal input triggers Ca²⁺ influx through AMPA receptors and voltage‐gated Ca²⁺ channels in oligodendrocytes

Abstract

Communication between neurons and developing oligodendrocytes (OLs) leading to OL Ca2+ rise is critical for axon myelination and OL development. Here, we investigate signaling factors and sources of Ca2+ rise in OLs in the mouse brainstem. Glutamate puff or axon fiber stimulation induces a Ca2+ rise in pre‐myelinating OLs, which is primarily mediated by Ca2+‐permeable AMPA receptors. During glutamate application, inward currents via AMPA receptors and elevated extracellular K+ caused by increased neuronal activity collectively lead to OL depolarization, triggering Ca2+ influx via P/Q‐ and L‐type voltage‐gated Ca2+ (Cav) channels. Thus, glutamate is a key signaling factor in dynamic communication between neurons and OLs that triggers Ca2+ transients via AMPARs and Cav channels in developing OLs. The results provide a mechanism for OL Ca2+ dynamics in response to neuronal input, which has implications for OL development and myelination.

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

“…Ca 2+ signalling has been shown to regulate many oligodendroglial cell functions, including proliferation, migration, process extension, differentiation, and myelination [ 86 , 96 , 110 , 136 , 137 , 138 , 139 ]. Intracellular Ca 2+ can increase in NG2 + cells throughout several mechanisms, such as direct influx through plasma membrane voltage-gated Ca 2+ channels (Cav) or ligand-gated channels [ 140 , 141 ], as mentioned below, or by the release from internal Ca 2+ stores [ 142 , 143 ] as well as Ca 2+ -permeable acid-sensing ion channel opening [ 144 ].…”

Excitotoxicity: Still Hammering the Ischemic Brain in 2020

“…OGD triggered AMPAR/KAR-mediated oligodendrocyte death in cultures (McDonald et al, 1998) or in adult brain slices (Tekkök and Goldberg, 2001). Ca 2+ -permeable AMPA receptors are expressed on oligodendrocytes (Matute et al, 1997;Barron and Kim, 2019) and may substantially mediate this excitotoxic vulnerability. Loss of cellular Zn 2+ homeostasis may contribute, as oligodendrocytes exposed to OGD developed increased [Zn 2+ ] i and subsequent death was reduced by a Zn 2+ chelator (Domercq et al, 2013).…”

Can Enhancing Neuronal Activity Improve Myelin Repair in Multiple Sclerosis?

“…However, there are multiple synaptic and non-synaptic signaling mechanisms that may play a role ( Hines et al, 2015 ; Mensch et al, 2015 ; Wake et al, 2015 ; Hughes and Appel, 2019 ). Electrically active axons release potassium which depolarizes OPCs and leads to the opening of voltage-gated calcium channels on OPCs ( Barron and Kim, 2019 ). Activated, unmyelinated axons release glutamate ( Kukley et al, 2007 ; Ziskin et al, 2007 ) which activates AMPA ( Barron and Kim, 2019 ), NMDA ( Doyle et al, 2018 ) as well as metabotropic glutamate receptors ( Wake et al, 2015 ) on oligodendroglia.…”

“…Electrically active axons release potassium which depolarizes OPCs and leads to the opening of voltage-gated calcium channels on OPCs ( Barron and Kim, 2019 ). Activated, unmyelinated axons release glutamate ( Kukley et al, 2007 ; Ziskin et al, 2007 ) which activates AMPA ( Barron and Kim, 2019 ), NMDA ( Doyle et al, 2018 ) as well as metabotropic glutamate receptors ( Wake et al, 2015 ) on oligodendroglia. Neuronal activity can also activate GABA and muscarinic receptors on OPCs ( Paez and Lyons, 2020 ).…”