Oligodendrocyte precursor cells (OPCs) differentiate into myelinating oligodendrocytes throughout life, allowing the formation of myelin during early development, but also following learning or demyelinating injuries. A number of factors are thought to regulate OPC proliferation and differentiation, including neuronal activity, which OPCs can sense and respond to through their voltage-gated ion channels and neurotransmitter receptors. Functional expression of these channels and receptors is often described as a defining feature of OPCs, although several reports suggest that OPCs exhibit diversity in their electrophysiological properties.

In this thesis, I investigate the diversity in OPC electrophysiological properties by performing whole-cell patch-clamp recordings of OPCs in different brain regions throughout the lifespan. I find that although OPCs first appear as a homogeneous population in the embryo, lacking voltage-gated ion channels and glutamate receptors, they gradually acquire these channels and receptors at different rates and become heterogeneous between and within brain regions. Correlating these electrophysiological data with RNA sequencing data, I propose that OPC diversity represents functional cellular states rather than different cell types.

In addition, I investigate how passive membrane properties change with age, and examine how AMPA but not kainate receptors differ with age. I further investigate whether OPCs can transition between different electrophysiological profiles, as would be the case if OPC diversity represented cell states. I focus on G protein-coupled neurotransmitter receptors as potential regulators of state transitions, as they can regulate OPC proliferation and differentiation, and were shown to modulate glutamate receptors in OPCs. I find that clemastine, a muscarinic receptor antagonist currently being tested to enhance myelin repair in Multiple Sclerosis clinical trials, alters glutamate receptors in OPCs, suggesting that cholinergic signalling can modulate OPC states. Moreover, driving G protein signalling in OPCs using Designer Receptors Exclusively Activated by Designer Drugs modifies their voltage-gated ion channels and glutamate receptors. Collectively, these data suggest that OPCs can transition between electrophysiological profiles in response to environmental cues such as G protein-coupled neurotransmitter signalling, and thus, that their diversity may represent functional cellular states.