A specific GABAergic synapse onto oligodendrocyte precursors does not regulate cortical oligodendrogenesis

Fast excitatory neurotransmission in the central nervous system occurs at specialized synaptic junctions between neurons, where a high concentration of glutamate directly activates receptor channels. Low-affinity AMPA (alpha-amino-3-hydroxy-5-methyl isoxazole propionic acid) and kainate glutamate receptors are also expressed by some glial cells, including oligodendrocyte precursor cells (OPCs). However, the conditions that result in activation of glutamate receptors on these non-neuronal cells are not known. Here we report that stimulation of excitatory axons in the hippocampus elicits inward currents in OPCs that are mediated by AMPA receptors. The quantal nature of these responses and their rapid kinetics indicate that they are produced by the exocytosis of vesicles filled with glutamate directly opposite these receptors. Some of these AMPA receptors are permeable to calcium ions, providing a link between axonal activity and internal calcium levels in OPCs. Electron microscopic analysis revealed that vesicle-filled axon terminals make synaptic junctions with the processes of OPCs in both the young and adult hippocampus. These results demonstrate the existence of a rapid signalling pathway from pyramidal neurons to OPCs in the mammalian hippocampus that is mediated by excitatory, glutamatergic synapses.

Formation of myelin, the electrical insulation on axons produced by oligodendrocytes, is controlled by complex cell-cell signaling that regulates oligodendrocyte development and myelin formation on appropriate axons. If electrical activity could stimulate myelin induction, then neurodevelopment and the speed of information transmission through circuits could be modified by neural activity. We find that release of glutamate from synaptic vesicles along axons of mouse dorsal root ganglion neurons in culture promotes myelin induction by stimulating formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase-dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience.

Adult neurogenesis arises from neural stem cells within specialized niches 1–3 . Neuronal activity and experience, presumably acting upon this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival 1, 3 . Whether local neuronal circuitry has a direct impact on adult neural stem cells is unknown. Here we show that in the adult hippocampus nestin-expressing radial glia-like quiescent neural stem cells 4–9 (RGLs) respond tonically to the neurotransmitter GABA via γ2 subunit-containing GABAA Rs. Clonal analysis 9 of individual RGLs revealed a rapid exit from quiescence and enhanced symmetric self-renewal after conditional γ2 deletion. RGLs are in close proximity to GAD67+ terminals of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of dentate PV+, but not somatostatin- or vasoactive intestinal polypeptide (VIP)-expressing, interneuron activity can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence following social isolation, an experience that induces RGL activation and symmetric division 8 . Our study identifies a niche cell-signal-receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.