Neuronal activity and remyelination: new insights into the molecular mechanisms and therapeutic advancements

Abstract

This article reviews the role of neuronal activity in myelin regeneration and the related neural signaling pathways. The article points out that neuronal activity can stimulate the formation and regeneration of myelin, significantly improve its conduction speed and neural signal processing ability, maintain axonal integrity, and support axonal nutrition. However, myelin damage is common in various clinical diseases such as multiple sclerosis, stroke, dementia, and schizophrenia. Although myelin regeneration exists in these diseases, it is often incomplete and cannot promote functional recovery. Therefore, seeking other ways to improve myelin regeneration in clinical trials in recent years is of great significance. Research has shown that controlling neuronal excitability may become a new intervention method for the clinical treatment of demyelinating diseases. The article discusses the latest research progress of neuronal activity on myelin regeneration, including direct or indirect stimulation methods, and the related neural signaling pathways, including glutamatergic, GABAergic, cholinergic, histaminergic, purinergic and voltage-gated ion channel signaling pathways, revealing that seeking treatment strategies to promote myelin regeneration through precise regulation of neuronal activity has broad prospects.

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

“…These cells represent 75% of all glial cells in the adult CNS. In addition to axonal myelination, OLs control extracellular potassium concentration and, as mentioned above, provide metabolic and trophic supply to myelin, secrete glial and brain-derived neurotrophic factors (GDNF and BDNF), and modulate the axonal growth [ 117 , 122 , 123 ], all of which highlight their importance in the functioning of CNS. Like microglia and astrocytes, OLs also express TLRs, which are considered of significant importance in myelin formation [ 58 , 124 , 125 ].…”

“…More recently, it was suggested that NG2 cells play a critical role in the modulation of neuroinflammation [ 131 ] and neurovascular unit formation during development [ 123 ] ( Figure 1 ). Although no TLRs have yet been identified in these cells, their importance in angiogenesis and oligodendrogenesis following acute ischemic stroke was reported [ 132 ].…”

“…OLs play a substantial role in CNS by forming a myelin sheath, which is critical in accelerating nerve conduction and maintaining the neuronal signaling process. Demyelination, due to the death of OLs and a loss of myelin sheaths, may lead to clinical disorders such as stroke, dementia, multiple sclerosis (MS), schizophrenia, and chronic cerebral hypoperfusion [ 123 ]. Increased myelin formation may be brought about by enhancing the signaling between neurons and OLs [ 235 , 236 ], which can lead to OPC differentiation, proliferation, and maturation, as well as neural pathway integrations [ 237 , 238 ].…”

“…Enhanced neuronal activity may be induced directly or indirectly by various techniques such as chemogenetics, optogenetics, sensory stimulation, transcranial stimulation [ 239 , 240 ], or potentially via pharmacological manipulation. Regarding the latter, and of relevance to the current topic, ACh involvement in myelin formation and the presence of both muscarinic and nAChRs in OLs was verified [ 123 , 241 , 242 ]. In fact, demyelination disorders are associated with defects in cholinergic anti-inflammatory signaling pathways mediated by α7nAChRs ( Figure 3 ).…”

“…Interestingly, whereas nicotinic stimulation boosts OPC maturation and myelin regeneration, muscarinic stimulation has the opposite effect in that OPC differentiation and myelin regeneration are retarded [ 21 , 214 ]. Nonetheless, the specific impact of nAChR signaling in relation to OL functioning in general and to PD in particular has yet to be fully revealed [ 123 ]. Moreover, since OLs also express TLRs, the elucidation of nAChRs’ interaction with TLRs in these cells may offer novel therapeutic targets not only in demyelination diseases but also in PD [ 121 ].…”