Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation

Abstract

Oligodendrocyte (OL) maturation and axon-glial communication are required for proper myelination in the developing brain. However, physiological properties of OLs remain largely uncharacterized in different brain regions. The roles of oligodendroglial voltage-activated Na+ channels (Nav) and electrical excitability in relation to maturation to the myelinating stage are controversial, although oligodendroglial excitability is potentially important for promoting axon myelination. Here we show spiking properties of OLs and their role in axon-glial communication in the auditory brainstem. A subpopulation of pre-myelinating OLs (pre-OLs) can generate Nav1.2-driven action potentials throughout postnatal development to early adulthood. In addition, excitable pre-OLs receive glutamatergic inputs from neighboring neurons that trigger pre-OL spikes. Knockdown of Nav1.2 channels in pre-OLs alters their morphology, reduces axon-OL interactions and impairs myelination. Our results suggest that Nav1.2-driven spiking of pre-OLs is an integral component of axon-glial communication and is required for the function and maturation of OLs to promote myelination.

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

“…In whole‐cell voltage‐clamp recordings, these GCaMP6f + cells displayed outwardly rectifying K + currents and, and 37.5% of cells showed transient inward Na + currents (Figure e). This electrophysiological profile aligns with what has previously been observed in pre‐myelinating OLs in the MNTB (Berret et al, ).…”

“…How do Ca 2+ ‐impermeable AMPAR currents contribute to Ca 2+ responses in OLs? Our previous study showed that glutamatergic input depolarized pre‐myelinating OLs and consequently activated voltage‐gated ion channels (Berret et al, ). We examined whether Ca 2+ influx via Ca v channels could be a source of glutamate‐induced Ca 2+ rise in OLs.…”

“…OL lineage cells express ionotropic glutamate receptors (e.g., AMPA and NMDA receptors) and receive glutamatergic input from neurons (Berret et al, ; Micu et al, ). We tested whether AMPA and NMDA receptors are involved in glutamate‐induced Ca 2+ transients in OLs using their antagonists.…”

“…Previous studies identified neuronal glutamate or GABA as potential mediators of neuron‐OL interaction (Bergles, Roberts, Somogyi, & Jahr, ; Kukley, Capetillo‐Zarate, & Dietrich, ; Lin & Bergles, ). In particular, OL lineage cells express Ca 2+ ‐permeable or Ca 2+ ‐impermeable AMPA receptors (AMPARs) and NMDA receptors, and thus can directly sense the glutamate release from neurons (Berret et al, ; Ge et al, ; Micu et al, ; Patneau, Wright, Winters, Mayer, & Gallo, ). Recent studies showed that inhibiting/knocking out neurotransmitter receptors in OLs impairs their response to neuronal activity and leads to alterations in OL development and function (Koudelka et al, ; Kougioumtzidou et al, ; Mensch et al, ), suggesting that glutamate can be an important signal for developing OLs to be able to sense the electrical activity of active axons.…”

“…Voltage‐gated Ca 2+ (Ca v ) channels are potential indirect effectors of glutamatergic input, because activation of AMPA receptors is able to depolarize and activate voltage‐gated ion channels in OL lineage cells (Berret et al, ; Káradóttir, Hamilton, Bakiri, & Attwell, ). Previous studies have reported the expression of L‐, N‐, and R‐type Ca v channels and the presence of their currents in OL lineage cells (Berger, Schnitzer, Orkand, & Kettenmann, ; Butt, ).…”