Cuprizone demyelination modifies neuron to oligodendrocyte progenitor cell synaptic networks

Oligodendrocyte progenitor cells (OPCs) receive direct synaptic input from neurons in the developing and adult brain. However, the diversity of the neuronal populations that synapse with OPCs is poorly characterised, and it remains unclear whether OPCs form synaptic connections with any axon in the vicinity or are more discriminating and form synapses with neurons that have specific structural or functional properties. Additionally, neuron-OPC synaptic communication has been implicated in the regulation of myelination and it is possible that the population of neurons that synapse with OPCs is altered by demyelination and during remyelination. Electrophysiological studies suggest that OPCs lose their synaptic connections as they differentiate into oligodendrocytes (OLs). However, mature myelinating OLs express genes encoding post-synaptic proteins and detect the activity of associated axons, making it possible they still receive synaptic input from neurons.

In Chapter 1, I review the neuroscience literature relevant to the structure and function of the neuron-OPC synapse, and examine the evidence surrounding synaptic communication between neurons and OLs. In Chapter 2, I used a modified rabies virus to perform genetically targeted monosynaptic viral tracing of OPCs located in the corpus callosum, and the population of neurons they are directly synaptically connected to, in healthy, cuprizone demyelinated, and remyelinating adult mice. The majority of neurons that synapsed onto callosal OPCs were ipsilateral cortical and CA1 hippocampal pyramidal neurons, and over 50% of the labelled cortical neurons were layer V pyramidal cells. Demyelination did not change the number of labelled neurons, but was associated with a switch in the type of neurons that synapsed with OPCs, with an increase in the proportion being identified in the ipsilateral cortex. Furthermore, demyelination was associated with a decrease in the number of synaptically connected layer V pyramidal neurons, and an increase in the number of synaptically connected layer II/III pyramidal neurons. These changes in connectivity were largely ameliorated by remyelination. These data suggest that callosal OPCs preferentially synapse with layer V pyramidal neurons in the healthy adult mouse cortex, but acute myelin loss drives competition between layer II/III and V pyramidal neurons, until myelin coverage can be restored.

In Chapter 3, I investigated the possibility that myelinating OLs retain synaptic connections with associated axons, by targeting infection of the monosynaptically restricted rabies virus to mature OLs in the body of the corpus callosum in adult mice. Following infection of OLs, a small population of pyramidal neurons was labelled, suggesting that OLs retain post-synaptic machinery within some, but not all, myelin internodes. Chapter 4 finishes with a discussion relating to the novel use of rabies virus mediated circuit tracing to study the pre-synaptic neurons that communicate with OPCs and OLs, neuronal populations that until now have remained poorly characterised, and how the data presented in this thesis add to the current knowledge of neuron-oligodendroglial synaptic connectivity.