Clemastine and metformin extend the window of NMDA receptor surface expression in ageing oligodendrocyte precursor cells.

In the central nervous system, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for ongoing myelination and myelin repair. With age, differentiation efficacy decreases and myelin repair fails; therefore, recent therapeutic efforts have focused on enhancing differentiation. Many cues are thought to regulate OPC differentiation, including neuronal activity, which OPCs can sense and respond to via their voltage-gated ion channels and glutamate receptors. However, OPCs' density of voltage-gated ion channels and glutamate receptors differs with age and brain region, and correlates with their proliferation and differentiation potential, suggesting that OPCs exist in different functional cell states, and that age-associated states might underlie remyelination failure. Here, we use whole-cell patch-clamp to investigate whether clemastine and metformin, two pro-remyelination compounds, alter OPC membrane properties and promote a specific OPC state. We find that clemastine and metformin extend the window of NMDAR surface expression, promoting an NMDAR-rich OPC state. Our findings highlight a possible mechanism for the pro-remyelinating action of clemastine and metformin, and suggest that OPC states can be modulated as a strategy to promote myelin repair.

Periods of synchronized myelin changes shape brain function and plasticity.

Myelin, a lipid membrane that wraps axons, enabling fast neurotransmission and metabolic support to axons, is conventionally thought of as a static structure that is set early in development. However, recent evidence indicates that in the central nervous system (CNS), myelination is a protracted and plastic process, ongoing throughout adulthood. Importantly, myelin is emerging as a potential modulator of neuronal networks, and evidence from human studies has highlighted myelin as a major player in shaping human behavior and learning. Here we review how myelin changes throughout life and with learning. We discuss potential mechanisms of myelination at different life stages, explore whether myelin plasticity provides the regenerative potential of the CNS white matter, and question whether changes in myelin may underlie neurological disorders.

Unraveling Myelin Plasticity.

Plasticity in the central nervous system (CNS) allows for responses to changing environmental signals. While the majority of studies on brain plasticity focus on neuronal synapses, myelin plasticity has now begun to emerge as a potential modulator of neuronal networks. Oligodendrocytes (OLs) produce myelin, which provides fast signal transmission, allows for synchronization of neuronal inputs, and helps to maintain neuronal function. Thus, myelination is also thought to be involved in learning. OLs differentiate from oligodendrocyte precursor cells (OPCs), which are distributed throughout the adult brain, and myelination continues into late adulthood. This process is orchestrated by numerous cellular and molecular signals, such as axonal diameter, growth factors, extracellular signaling molecules, and neuronal activity. However, the relative importance of, and cooperation between, these signaling pathways is currently unknown. In this review, we focus on the current knowledge about myelin plasticity in the CNS. We discuss new insights into the link between this type of plasticity, learning and behavior, as well as mechanistic aspects of myelin formation that may underlie myelin plasticity, highlighting OPC diversity in the CNS.

Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age.

Oligodendrocyte progenitor cells (OPCs), which differentiate into myelinating oligodendrocytes during CNS development, are the main proliferative cells in the adult brain. OPCs are conventionally considered a homogeneous population, particularly with respect to their electrophysiological properties, but this has been debated. We show, by using single-cell electrophysiological recordings, that OPCs start out as a homogeneous population but become functionally heterogeneous, varying both within and between brain regions and with age. These electrophysiological changes in OPCs correlate with the differentiation potential of OPCs; thus, they may underlie the differentiational differences in OPCs between regions and, likewise, differentiation failure with age.