Cholinergic signaling in myelination

Abstract

There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential of manipulating ACh signaling to promote remyelination, and the broader interest in neurotransmitter signaling in activity-dependent myelination. Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors at different stages of development, and acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter. This review traces the history of research on ACh signaling in Schwann cells, oligodendrocytes, and in the myelin sheath, and summarizes current knowledge on the intracellular signaling and functional consequences of ACh signaling in myelinating glia. Implications of ACh in diseases, such as Alzheimer's disease, multiple sclerosis, and white matter toxicity caused by pesticides are considered, together with an outline of major questions for future research. GLIA 2017;65:687-698.

Oligodendrocyte involvement in Gulf War Illness

“…Our finding that DFP decreases maturation of oligodendrocytes is consistent with the current literature about the role of ACh signaling on oligodendrocyte development (Fields et al, ). In MS human clinical trials and MS animal models, inhibition of muscarinic receptors and consequent inhibition of ACh signaling is shown to promote remyelination (Abiraman et al, ; Green et al, ; Li et al, ; Liu et al, ; Mei et al, ; Welliver et al, ).…”

“…Similarly, AChE was expressed on the membrane of OPCs grown for 24 hr in growth medium (Figure b) and oligodendrocytes grown for 3 days in differentiation medium (Figure c). The function of AChE in oligodendrocytes is unclear (Fields et al, ), but sarin gas and other AChE inhibitors would act on both neuronal and glial AChEs.…”

“…For example, blocking vesicular release of the neurotransmitter glutamate from axons by Botulinum toxin treatment, inhibits local protein synthesis of the major protein in myelin, myelin basic protein (MBP), and impairs induction of myelination on electrically active axons (Wake, Lee, & Fields, 2011). Activity-dependent myelination has been primarily studied in the context of glutamatergic signaling (Fields, 2015;Kukley, Capetillo-Zarate, & Dietrich, 2007;Wake et al, 2011;Wake et al, 2015), but the neurotransmitter acetylcholine (ACh) has recently been suggested to influence oligodendrocyte progenitor cell (OPC) proliferation, differentiation, and myelination (De Angelis, Bernardo, Magnaghi, Minghetti, & Tata, 2012;Fields, Dutta, Belgrad, & Robnett, 2017). In the CNS, cholinergic neurons in the basal forebrain extend long-range axons to broadly innervate the entire cerebral cortex (Luchicchi, Bloem, Viaña, Mansvelder, & Role, 2014;Wu, Williams, & Nathans, 2014).…”

“…Similarly, AChE was expressed on the membrane of OPCs grown for 24 hr in growth medium (Figure 1b) and oligodendrocytes grown for 3 days in differentiation medium(Figure 1c). The function of AChE in oligodendrocytes is unclear(Fields et al, 2017), but sarin gas and other AChE inhibitors would act on both neuronal and glial AChEs.We performed live-cell calcium imaging to determine if the mAChRs expressed on OPCs were functional. M1, M3, and M5 receptors signal via activating intracellular Ca 2+ , but M2 and M4 receptors signal through cAMP.…”

Cholinergic Potentiation and Audiovisual Repetition-Imitation Therapy Improve Speech Production and Communication Deficits in a Person with Crossed Aphasia by Inducing Structural Plasticity in White Matter Tracts

“…These divergent changes are comparable with the results of experimental studies in animals treated with psychoactive drugs (Kolb and Gibb, 2014, 2015) and in healthy human subjects after training (see references in May, 2011), which showed not only that plastic changes are region-specific, but also that different regions can express opposite changes. Moreover, the fact that the right FAT was anatomically intact can justify incremental changes on its microstructure in response to pharmacological and behavioral manipulation perhaps due to optimization of cholinergic activity, activity-dependent myelination, glial rearrangement, formation of new synapsis, or increased vasculature (May, 2011; Fields et al, 2017). …”