Glial Cells in Health and Disease: Impacts on Neural Circuits and Plasticity

Shirin Hosseini ^1* Poonam Thakur ^2* David Cedeno ^3* Masoud Fereidoni ^4* Mahmoud Elahdadi Salmani ^5*

• ¹ Department of Cellular Neurobiology, Zoological Institute, TU Braunschweig, Braunschweig, Germany
• ² School of Biology, IISER Thiruvananthapuram, Thiruvananthapuram, Kerala, India
• ³ Department of Psychology, Illinois Wesleyan University, Bloomington, IL, USA, Illinois, United States
• ⁴ Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
• ⁵ School of Biology, Damghan University, Damghan, Iran

This research topic has markedly enhanced the current understanding of the role of glial cells on pathological conditions of both the central nervous system (CNS) and peripheral nervous system (PNS) (Verkhratsky et al., 2014; Tan et al. 2021). The diversity of these conditions is largely dictated by glial cells in the particular regions of the affected neural tissue and the distinct interactions of glial cells and other cells. Investigating the common molecular mechanisms underlying these conditions can illuminate pathways for developing innovative therapeutic strategies.This comprehensive analysis synthesizes findings from the pivotal studies in this research topic, highlighting critical intersections between neuroimmunology and cellular neurophysiology. The study of Kleidonas et al. delineates the acute effects of elevated ammonia levels, relevant to liver dysfunction, on the synaptic transmission of CA1 neurons in mouse entorhino-hippocampus tissue. Elevated ammonia suppresses neuronal action due to their impact on astrocyte functionality, highlighting the key regulatory role that astrocytes play in maintaining synaptic homeostasis, through modulating excitatory synapses. Importantly, it was observed that the inhibition of glutamine synthetase, an astrocytic enzyme, mitigates the downregulation of excitatory transmissions, reinforcing the pivotal role of astrocytes in neural function.Concurrently, the study by Gabele et al. delves into the sex-specific neurotropic effects of influenza A virus (H7N7 strain) on mouse hippocampal cells. It unveils that female-derived cells exhibit a more pronounced innate immune response, marked by elevated interferon-β and chemokine secretion, leading to differential microglial activation and morphological neural changes compared to male-derived cells. This sex-specific variation in immune response highlights the intricate dynamics of pathogen or stressor-host interactions within the CNS, which warrants careful consideration of sex-specific effect in future research endeavors (Chen et al., 2018).The review study by Kveštak et al. extends the discussion to Innate Lymphoid Cells (ILCs), which, although a minor component of the CNS under physiological conditions, infiltrate CNS parenchyma during neuroinflammatory and infectious scenarios. ILCs, through interactions with other immune cells, including astrocytes and microglia, modulate CNS tissue responses, thereby influencing the outcomes of autoimmune diseases and viral infections. This understanding of ILC function aligns with the findings of the previous two studies suggesting potential synergistic effects between cellular stress responses of peripheral immune system and immune modulation in the CNS.The interactions between glial cells and neurons in the PNS play a critical role alongside those in the CNS (Müller et al., 2025). The study of Mohamed et al. enhances our understanding of the multifaceted roles of protein kinase C epsilon type (PKCε) within the PNS. While PKCε is already recognized for its involvement in cancer progression, this study uncovers a novel function in Schwann cells (SCs), the glial cells of the PNS, which are crucial for peripheral nerve regeneration and functionality. This work elucidates the capacity of PKCε to modulate SCs proliferation, migration, and differentiation, highlighting its role in facilitating the transition between proliferative and differentiated states, as well as an epithelial-mesenchymal transition-like process. The identification of a BDNF-TrkB-PKCε autocrine signaling axis provides valuable insights into the molecular mechanisms regulating SCs plasticity. This groundbreaking work suggests that targeting this pathway may open new therapeutic avenues for addressing peripheral nerve injuries, neuropathic pain, peripheral nerve tumors, and related neuropathies, thereby broadening the scope for intervention in PNS-related disorders.In the work conducted by Schröder et al. a rational drug design approach was employed to address Multiple Sclerosis (MS), a chronic, autoimmune, demyelinating disease of the CNS; although clinical studies have demonstrated PNS involvement in a subgroup of patients (Adamec et al., 2021). The study focused on polysialic acid (polySia), a glycan recognized for its immunomodulatory properties, demonstrating its potential benefits in the upregulation of myelin. Notably, the application of polySia with a chain length of DP24–30 in organotypic murine brain slices was found to significantly enhance remyelination. This effect is mediated through the modulation of microglial activation via the inhibitory immune receptor Siglec-E. Furthermore, the findings indicate that polySia effectively reduces proinflammatory responses in microglia, fostering an environment that supports myelin regeneration. By elucidating the immunomodulatory and pro-regenerative capabilities of polySia, this study contributes to a deeper understanding of the mechanisms underlying myelin repair, establishing polySia as a promising therapeutic target for treating demyelinating diseases such as MS.Remarkably, the investigation of polySia on SCs is particularly intriguing, as polySia has been shown to enhance SCs proliferation and migration, thereby promoting peripheral nerve regeneration and myelination, which could offer novel therapeutic insights for neuropathic conditions and nerve injuries.In the mini-review by Gjervan et al., an alternative strategy for myelin repair is presented, focusing on claudin-11, a crucial protein of tight junctions within the myelin sheath. Recent studies have elucidated that heterozygous stop-loss mutations in the CLDN11 gene are implicated in the etiology of hypomyelinating leukodystrophy 22 (HLD22), a genetic disorder characterized by impaired myelination. Investigations conducted in claudin-11-deficient mouse models have demonstrated significant physiological impairments, including delayed nerve transmission, auditory deficits, and male sterility, thereby revealing the multifaceted roles of this protein. These findings underscore the urgency for further research aimed at elucidating the full spectrum of claudin-11's functions and advancing the development of effective therapeutic interventions, not only for HLD22 and related conditions but also for other demyelinating diseases.Together, the articles in this research topic underscore a nuanced paradigm where glial cells, peripheral immune cells, and neurons interact differentially under metabolic, pathologic and infectious stressors, influenced by inherent sex-based immunological differences (Figure 1). This integrative perspective advances our understanding of PNS and CNS pathophysiology, particularly in elucidating mechanisms underlying synaptic regulation, immune cell interactions, and the development of potential therapeutic interventions targeting nervous system disorders in the context of acute and chronic neuroinflammatory conditions.