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In the developing and adult brain, oligodendrocyte precursor cells (OPCs) are influenced by neuronal activity: they are involved in synaptic signaling with neurons, and their proliferation and differentiation into myelinating glia can be altered by transient changes in neuronal firing. An important question that has been unanswered is whether OPCs can discriminate different patterns of neuronal activity and respond to them in a distinct way. Here, we demonstrate in brain slices that the pattern of neuronal activity determines the functional changes triggered at synapses between axons and OPCs. Furthermore, we show that stimulation of the corpus callosum at different frequencies in vivo affects proliferation and differentiation of OPCs in a dissimilar way. Our findings suggest that neurons do not influence OPCs in “all-or-none” fashion but use their firing pattern to tune the response and behavior of these nonneuronal cells., Author summary Oligodendrocytes are glial cells of the central nervous system. One of their major tasks is to enwrap neuronal axons with myelin, providing electrical insulation of axons and a dramatic increase in the speed of nerve impulse propagation. Oligodendrocytes develop from oligodendrocyte precursor cells (OPCs). Self-renewal of OPCs, their differentiation into oligodendrocytes, and the process of myelin synthesis are influenced by neuronal activity. Furthermore, OPCs receive glutamatergic synaptic input from neurons. Neuronal activity in vivo is highly variable depending on the brain region, input stimulus, and/or behavioral task that an animal or human has to perform in everyday life. Therefore, it is important to understand whether different types of neuronal activity affect development and function of oligodendrocyte lineage cells in a distinct way. In this study, we demonstrate that the amount and the timing of glutamate release at synapses between neurons and OPCs, the properties of the subsequent ionic current through glutamate receptors in OPC membrane, as well as the extent of OPCs’ self-renewal and differentiation into oligodendrocytes differ depending on the frequency and duration of neuronal activity. Hence, the pattern of neuronal activity rather than just presence or absence of activity is an important parameter that determines development and function of oligodendroglial cells.