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.
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.
The nervous system plays an increasingly appreciated role in the regulation of cancer. In malignant gliomas, neuronal activity drives tumor progression not only through paracrine signaling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF)1–3, but also through electrophysiologically functional neuron-to-glioma synapses4–6. Malignant synapses are mediated by calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in both pediatric and adult high-grade gliomas4, 5, and consequent depolarization of the glioma cell membrane drives tumor proliferation4. The nervous system exhibits plasticity of both synaptic connectivity and synaptic strength, contributing to neural circuit form and functions. In health, one factor that promotes plasticity of synaptic connectivity7, 8 and strength9–13 is activity-regulated secretion of the neurotrophin BDNF. Here, we show that malignant synapses exhibit similar plasticity regulated by BDNF-TrkB (tropomyosin receptor kinase B) signaling. Signaling through the receptor TrkB14, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. This potentiation of malignant synaptic strength shares mechanistic features with the long-term potentiation (LTP)15–23 that is thought to contribute to memory and learning in the healthy brain22 24–27 28, 29. BDNF-TrkB signaling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of TrkB in human glioma cells exerts growth inhibitory effects in vivo and in neuron:glioma co-cultures that cannot be explained by classical growth factor signaling alone. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma (DIPG). Taken together, these findings indicate that BDNF-TrkB signaling promotes malignant synaptic plasticity and augments tumor progression.
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