Demyelination produces a shift in the population of cortical neurons that synapse with callosal oligodendrocyte progenitor cells.

Oligodendrocyte progenitor cells (OPCs) receive synaptic input from a diverse range of neurons in the developing and adult brain. Understanding whether the neuronal populations that synapse with OPCs in the healthy brain is altered by demyelination and / or remyelination may support the advancement of neuroprotective or myelin repair strategies being developed for demyelinating diseases such as multiple sclerosis. To explore this possibility, we employed cre-lox transgenic technology to facilitate the infection of OPCs by a modified rabies virus, enabling the retrograde monosynaptic tracing of neuron-OPC connectivity. In the healthy adult mouse, OPCs in the corpus callosum primarily received synaptic input from ipsilateral cortical neurons. Of the cortical neurons, ∼50% were layer V pyramidal cells. Cuprizone demyelination reduced the total number of labelled neurons. However, the frequency / kinetics of mini excitatory post-synaptic currents recorded from OPCs appeared preserved. Of particular interest, demyelination increased the number of labelled layer II/III pyramidal neurons also increased at the expense of layer V pyramidal neurons; a change that was largely ameliorated by remyelination. These data suggest that in the healthy adult mouse brain, callosal OPCs primarily receive synaptic input from cortical layer V pyramidal neurons. However, callosal demyelination is associated with a population switch and OPCs equally synapse with layer II/III and V pyramidal neurons to synapse with OPCs, until myelin is restored.Significance statement In the CNS, myelination and remyelination involve the differentiation of oligodendrocyte progenitor cells (OPCs) into new oligodendrocytes (OLs), some of which survive to mature and myelinate axons. Throughout this process, neurons communicate with the OPCs and developing OLs. We show that OPCs in the corpus callosum of adult mice, predominantly receive synaptic input from layer V cortical pyramidal neurons. However, they synapse equally with layer II/III and layer V neurons following cuprizone demyelination, suggesting that the highly motile OPC processes select alternative pre-synaptic sites. 5-weeks of remyelination sees OPC connectivity bias return to layer V neurons. This provides critical insight into neuron-OPC communication and cellular interactions that are impacted in demyelinating diseases such as multiple sclerosis.