Mechanisms of Serotonergic Modulation of Glial Cell Functions in the Recovery Period After Spinal Cord Injury

Spinal cord injury (SCI) leads to severe disability in patients, and one of the key obstacles to the recovery of lost functions is inefficient axonal remyelination. The high sensitivity of oligodendrocytes to secondary damage, the formation of a glial scar, and chronic neuroinflammation sustained by pro-inflammatory/neurotoxic microglia create a physical and chemical barrier to neuroplasticity processes. This review summarizes current knowledge on the ability of the serotonergic system to modulate the functional state of the main types of glial cells: oligodendrocytes, astrocytes, and microglia. It is shown that oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes express 5-HT1A, 5-HT2A, and 5-HT7 receptors, whose activation can either stimulate differentiation or suppress migration or induce apoptosis, depending on the developmental stage and microenvironment. In astrocytes, serotonin, predominantly via 5-HT2B receptors, limits pro-inflammatory transformation, reduces NLRP3 inflammasome activity, and stimulates BDNF production, glycogenolysis, and lactate release. In microglia, serotonergic stimulation (via 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT7 receptors) attenuates the pro-inflammatory phenotype by suppressing production of TNF-α and IL-1β. To date, the proposed therapeutic strategies include: the use of 5-HT receptor agonists/antagonists and transplantation of serotonergic cells (hNT2.19 and RN46A-B14 lines), which reduce neuropathic pain and promote motor function recovery in rodents after SCI. The key limitations for the effective translation of these findings into clinical practice are the heterogeneity of effects of different serotonin receptor subtypes, the dependence of outcomes on the time after injury, and pronounced species specificity. Thus, the serotonergic system represents a promising but complex target for inducing neuroplasticity processes; success requires the development of subtype-selective ligands and treatment protocols that take into account the stages of pathological processes in SCI.