Neuronal Activity Changes the Number of Neurons that are Synaptically Connected to OPCs.

The timing and specificity of oligodendrocyte myelination during development, as well as remyelination after injury or immune attack, remain poorly understood. Recent work has shown that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. In this study, we investigated the importance of these neuroglial connections in myelination during development and during neuronal plasticity in the mouse hippocampus. We utilized chemogenetic tools and viral monosynaptic circuit tracing to analyze these connections and to examine oligodendrocyte progenitor cells (OPC) proliferation, myelination, synapse formation, and neuronal-glial connectivity in vivo after increasing or decreasing neuronal activity levels. We found that increasing neuronal activity led to greater OPC activation and proliferation. Modulation of neuronal activity also altered the organization of neuronal-glial connections: while it did not impact the total number of RabV-labeled neuronal inputs, or the number of RabV-labeled inhibitory neuronal inputs, it did alter the number of RabV-labeled excitatory neuron to OPC connections. Overall, our findings support the idea that neuronal activity plays a crucial role in regulating OPC proliferation and activation as well as the types of neuronal inputs to OPCs, indicating that neuronal activity is important for OPC circuit composition and function. Significance Statement Neuronal degeneration, traumatic brain injury, and multiple sclerosis all share a common clinical feature: loss of myelin on the axons of neurons, which is critical for accurate and rapid conduction of information throughout the CNS. Understanding the maturation of the glial cells that make myelin is critical to develop therapeutics to restore myelin and treat demyelinating diseases and brain injury. Our work provides insight on the role of neuronal activity in cuing OPC proliferation, activation, and neuron to glia synapse formation, expanding our growing knowledge about the importance of synaptic interactions between neurons and glia in the brain.