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 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, similar to 50% were layer V pyramidal cells. Cuprizone demyelination reduced the total number of labeled neurons. However, the frequency/ kinetics of mini-excitatory postsynaptic currents recorded from OPCs appeared preserved. Of particular interest, demyelination increased the number of labeled layer II/III pyramidal neurons and 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.