Emerging Roles of Cholinergic Receptors in Schwann Cell Development and Plasticity

Abstract

The cross talk between neurons and glial cells during development, adulthood, and disease, has been extensively documented. Among the molecules mediating these interactions, neurotransmitters play a relevant role both in myelinating and non-myelinating glial cells, thus resulting as additional candidates regulating the development and physiology of the glial cells. In this review, we summarise the contribution of the main neurotransmitter receptors in the regulation of the morphogenetic events of glial cells, with particular attention paid to the role of acetylcholine receptors in Schwann cell physiology. In particular, the M2 muscarinic receptor influences Schwann cell phenotype and the α7 nicotinic receptor is emerging as influential in the modulation of peripheral nerve regeneration and inflammation. This new evidence significantly improves our knowledge of Schwann cell development and function and may contribute to identifying interesting new targets to support the activity of these cells in pathological conditions.

Emerging role of extracellular vesicles and exogenous stimuli in molecular mechanisms of peripheral nerve regeneration

“…The crosstalk between axons and SCs is also regulated by cholinergic receptors, these receptors respond to neurotransmitters such as Acetylcholine (ACh), Glutamate, γ-aminobutyric acid (GABA), and Adenosine/ATP. In particular, the M2 muscarinic receptors and the α7 nicotinic acetylcholine receptors (α7 nAChRs) influence SC plasticity and function in PNR ( Piovesana et al, 2022 ). Activation of these α7 nAChRs is facilitated by neurotransmitter ACh, which is expressed and released by motor and sensory nerves, further suggesting its involvement in the SC-axon crosstalk.…”

“…Intriago et al reported an increase in α7 nAChRs expression in SCs 24 h following PNI, which reduced the expression of proinflammatory IL-6 cytokine, hence, regulating the inflammatory response. Furthermore, the increase in α7 nAChRs expression correlates with a decrease in c-Jun expression, which is a transcription factor known to mediate SC plasticity ( Salazar Intriago et al, 2021 ; Piovesana et al, 2022 ).…”

“…Zhao et al reported that the significantly increased Src levels in SCs after injury promote axonal elongation through a crosstalk between regenerating axons and SCs ( Zhao et al, 2003 ; Melfi et al, 2017 ). The activation of FAK/Src in SCs involves GABA-A-dependent mechanisms, as the binding of the neuroactive steroid Allopregnanolone (ALLO) to the GABA-A receptors expressed by SCs leads to a series of downstream intracellular signaling pathway activation, one of which is FAK/Src, as illustrated in Figure 2Ai ( Colciago et al, 2020 ; Piovesana et al, 2022 ). ALLO is additionally found to upregulate SC proliferation in vitro following the binding of GABA-A and the modulation of excitatory amino acid transporter 1 (EAAC1).…”

“…ALLO is additionally found to upregulate SC proliferation in vitro following the binding of GABA-A and the modulation of excitatory amino acid transporter 1 (EAAC1). The modulatory role of ALLO is demonstrated through the GABA-A-mediated activation of protein kinase C (PK-C), leading to rapid upregulation of EAAC1 and Src levels in SCs, followed by increased EAAC1 exocytosis and modification of SC morphology ( Perego et al, 2012 ; Piovesana et al, 2022 ). This increase in Src levels results in an increase of p-FAK signaling, which drives SC proliferation.…”

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Thus, given the important role of glial cells in the pathogenesis of PD [ 17 , 18 , 19 , 20 ] and the implicated nAChR regulation of these cells [ 17 , 18 , 21 ], our aim in this review is to provide not only an update on glial nAChRs’ role in glial function but also the potential exploitation of this knowledge in identifying novel targets for this devastating disease.…”