Novel Toolboxes for the Investigation of Activity-Dependent Myelination in the Central Nervous System

Abstract

Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity-dependent myelination have not been fully elucidated. Myelination is a multi-step process that involves the proliferation and differentiation of oligodendrocyte precursor cells followed by the initial contact and ensheathment of axons by mature oligodendrocytes. Conventional end-point studies rarely capture the dynamic interaction between neurons and oligodendrocyte lineage cells spanning such a long temporal window. Given that such interactions and downstream signaling cascades are likely to occur within fine cellular processes of oligodendrocytes and their precursor cells, overcoming spatial resolution limitations represents another technical hurdle in the field. In this mini-review, we discuss how advanced genetic, cutting-edge imaging, and electrophysiological approaches enable us to investigate neuron-oligodendrocyte lineage cell interaction and myelination with both temporal and spatial precision.

Keywords: AMPA receptor; activity-dependent myelination; glutamate uncaging; local stimulation; time-lapse imaging.

Figure 1

Genetic approaches to manipulate the expression of AMPA receptors in OPCs. Synaptic vesicles containing glutamate (green dots) will be released upon the arrival of action potentials. The release of glutamate will activate post-synaptic AMPA receptors and evoke a post-synaptic current (dark gray traces). (A) Genetically silencing all AMPA receptor subunits will diminish AMPA receptor-mediated postsynaptic currents. (B) Silencing the GluA2 subunit alone will increase Ca²⁺ permeability through AMPA receptors. (C) Expressing the GluA2-containing AMPA receptor will block the Ca²⁺ entry through AMPA receptors. OPCs, oligodendrocyte precursor cells.

Figure 2

Locally activate postsynaptic receptors within OPC processes via either (A) local electrical stimulation or (B) 2-photon glutamate uncaging. (A) The mono-polar stimulating electrode can be placed in close proximity (~5 μm) to the target OPC process (dash circle) to only stimulate the axons passing the process segment. (B) Acute brain slices are bathed with caged-glutamate containing bath solution. The 2-photon uncaging laser (~720 nm) is pointed to the target locations by galvo scan mirrors inside the scan head. A brief uncaging laser pulse (0.6–1 ms) will uncage the caged-glutamate compound within the 2-photon excitation volume (blue shaded circle) and evoke an electrical response from post-synaptic neurotransmitter receptors (dark gray trace).