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From cellular diversity to coordinating nervous system function: the next frontier in non-neuronal cell biology
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DOI：10.3389/fncel.2026.1934284.png)
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Abstract
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Non-neuronal cells do not simply detect neuronal activity; they can regulate neuronal plasticity and behaviour. One way these cells regulate neuronal plasticity is by removing synapses. For example; microglia clear synapses during development and disease through complement-dependent and independent mechanisms (Pereira-Iglesias et al.; 2025). These processes are regulated by neuronal activity. Microglial synaptic clearance has been understood in several circuits; but how this synaptic clearance relates more broadly to brain and spinal cord plasticity; cognition and behaviour is still being defined. Astrocytes and oligodendrocyte progenitor cells (OPCs) are also involved in synapse removal (Chung et al.; 2013;Lee et al.; 2021;Auguste et al.; 2022); yet less is known about how the coordination of synapses occurs between glial cell types. In addition to synaptic restructuring; non-neuronal cells can change neuronal plasticity by other mechanisms. Microglia regulate the breakdown of ATP to adenosine to modulate neuronal activity (Badimon et al.; 2020). Non-neuronal cells also produce and maintain perineuronal nets (Tewari et al.; 2022); impacting neuronal plasticity (Tewari et al.; 2024). For example; the degradation of perineuronal nets after peripheral nerve injury by microglia promotes spinal nociceptive circuits that drive pain hypersensitivity (Tansley et al.; 2022). How microglia regulate perineuronal nets during disease and homeostatic processes; with implications for behaviour and cognition; is also an exciting area of research.Another emerging area of glial-neuronal interaction concerns how oligodendrocyte lineage changes following experience and learning; known as myelin plasticity (Xin and Chan; 2020). Myelin is continually changed throughout lifespan (Hughes et al.; 2013;Hill et al.; 2018;Hughes et al.; 2018) in response to sensory experience or neuronal activity (Gibson et al.; 2014;Hughes et al.; 2018). Myelin plasticity is critical for different types of learning and memory. For example; the conditional blockade of oligodendrocyte production impairs memory consolidation and motor learning; potentially other neurological functions (McKenzie et al.; 2014;Pan et al.; 2020;Steadman et al.; 2020). However; what oligodendrocyte function accounts for these cognitive roles is still unknown. Potentially myelin alters conduction velocity and circuit synchrony; contributing to these behavioural consequences. Alternatively; other oligodendrocyte roles; such as their metabolic coupling to axons (Micu et al.; 2018); may affect learning; memory; or cognition. Understanding how oligodendrocytes contribute to behaviour is important given the link with myelinating cells and to neurodegenerative and psychiatric diseases such as schizophrenia (Gibson et al.; 2018;Nave et al.; 2023).Given the critical roles of non-neuronal cells during homeostasis; the loss of these functions in disease or the acquisition of new roles are central to all neurological diseases. For example; microglia constantly extend their processes into their area of influence; responding to hundreds; if not thousands; of factors (Hickman et al.; 2013). During disease; the homeostatic signature of microglia and their surveillant roles shift; microglia transition into many different disease-related states (Zia et al.; 2020;Healy et al.; 2022;Paolicelli et al.; 2022). These states represent a complex response that can be initiated by damage-related molecules such as myelin debris; dead cells; or amyloid (Dolan et al.; 2022;Zia et al.; 2022). By taking up these diseaserelated roles; microglia shift their functions in conjunction with state changes. Whether these states all have distinct functions is suspected based on the unique expression of different ligands; but the functions of these microglial states remain largely unexplored. One of the defining challenges of the next decade will be moving beyond transcriptomic descriptions of microglial states toward identifying the molecular switches that govern state transitions-also known as microglial plasticity-and determining which states causally influence neurological disease. In chronic diseases; microglia can form foamy cells with lipid-rich inclusions (van der Vliet et al.; 2026); as in atherosclerotic plaques; which may represent a point of microglial exhaustion (Chen et al.; 2025;Ziaee et al.; 2026). Another major challenge will be to understand the biological underpinnings of how microglia fatigue; or become exhausted; in chronic conditions; whether these foamy microglia represent an exhausted or a more reversible 'full' microglial state; and whether this is relevant to aging and neurodegenerative conditions.Emerging is the understanding that all non-neuronal cells shift into different states. Disease-related states are being identified; including disease-associated oligodendrocytes (DAO); disease-associated OPCs; and disease-associated astrocytes (Falcao et al.; 2018;Jakel et al.; 2019;Habib et al.; 2020;Absinta et al.; 2021;Patani et al.; 2023). These disease-associated states are diverse; but likely none more so than in astrocytes; where many reactive astrocytic states vary with pathology (Patani et al.; 2023). These disease-associated states often alter gene expression patterns indicative of innate immune activation; cytokine and chemokine secretion; or type I interferon signalling (Falcao et al.; 2018;Kirby et al.; 2019;Habib et al.; 2020;Absinta et al.; 2021;Pandey et al.; 2022). During disease conditions; non-neuronal cells respond by upregulating inflammatory molecules involved in antigen presentation; such as MHC molecules (Falcao et al.; 2018;Kirby et al.; 2019;Absinta et al.; 2021;Hill et al.; 2026). Other common attributes include lipid remodelling and an oxidative stress response (Falcao et al.; 2018;Ioannou et al.; 2019;Jakel et al.; 2019;Kirby et al.; 2019;Absinta et al.; 2021;Guttenplan et al.; 2021;Hasel et al.; 2021;Pandey et al.; 2022). Importantly; the identity of disease-associated states consistently reflects a loss of homeostatic identity; suggesting that; in addition to gaining immune functions in disease; non-neuronal cells lose homeostatic functions. Future work should define these disease-associated states using orthogonal tools; in diverse disease conditions; to compare commonalities and differences. Disease-associated cells may gain new functions; but it is also critical to understand how loss of homeostatic functions relates to disease pathogenesis. Understanding non-neuronal cells in disease states must also move beyond defining diseaserelated states and work towards uncovering the triggers that transition non-neuronal cells into these disease-associated states; identifying the functions of these states; and determining which represent adaptive repair programs and which actively drive pathology.Beyond the major glial populations of the CNS; important advances are also emerging for non-neuronal cells in the peripheral nervous system (PNS); including Schwann cells; satellite glial cells; enteric glia; and peripheral nerve-resident immune cells. These cells regulate axonal maintenance; regeneration; neuroimmune communication; and neuronal excitability; highlighting the broad importance of non-neuronal biology throughout the nervous system. While major glial cells have many known functions; less investigated are the other CNS cells that largely populate CNS boundaries. For example; in the CNS; various cells surround ventricles and line blood vessels. Additional cells are found layering the pia matter and within the arachnoid and meninges. For example; within the choroid plexus; surrounding blood vessels; and lining the pia are populations of macrophages referred to as border-associated macrophages (BAM) (Goldmann et al.; 2016;Ajami et al.; 2018;Kierdorf et al.; 2019). Several other barrier cell types are found in the CNS; including endothelial cells; pericytes; choroid plexus epithelial cells; arachnoid barrier cells; ependymal cells; and fibroblasts. Together; these cells regulate molecular transport; immune surveillance; tissue homeostasis; and communication between the CNS; the lymphatics; and the circulation. In addition to barrier cells; there is a complex atlas of adaptive and innate immune cells within the leptomeningeal space and dura mater of the CNS (Mrdjen et al.; 2018;Rustenhoven and Kipnis; 2022). While the anatomy of these structures and the diverse cellular components are being defined; how these cells contribute during CNS development; homeostasis; and disease is an emerging research area. Future research investigating the different ways in which barrier cells affect CNS functions; immune cell trafficking; debris clearance; and immune cell activity will provide a new understanding and likely novel targets for treating neurological diseases.Tools are expanding our understanding of non-neuronal cells. The next decade of nonneuronal cell research will move beyond descriptive cellular atlases toward mechanistic understanding of how diverse glial and border-associated cell populations coordinate neural circuit function; repair; and disease progression. The next generation of approaches; including spatial transcriptomics; in vivo imaging; perturbation sequencing; and multimodal profiling; will allow investigators to determine how non-neuronal cells communicate; transition between functional states; and causally regulate behaviour and disease. New advances; such as single-cell proteomics; will better define how cell states relate to cellular function. Needed now in the field of non-neuronal cells are tools that enable circuitry-specific manipulation of non-neuronal cells. Tools to define how non-neuronal cells impact specific neurons or circuits will usher in a new era of discovery; linking non-neuronal cells to specific CNS functions.Over the past century; neuroscience has largely been neuron-centric. The coming decade may instead define neuroscience through understanding how diverse non-neuronal cells coordinate nervous system function across health; ageing and disease. Historically; astrocytes; microglia; oligodendrocytes and OPCs have largely been investigated independently. Increasingly; however; evidence suggests these cells function as coordinated cellular networks that collectively sense neuronal activity; maintain homeostasis and orchestrate responses to injury. Understanding this intercellular communication may ultimately prove more informative than studying individual cell types in isolation. Neurological conditions represent a breakdown of homeostasis due to injury; infection; or disease. Given the fundamental role of non-neuronal cells in homeostasis; expanding our knowledge of these critical cells will lead to a greater understanding of disease mechanisms and new strategies to treat neurological conditions. With so much passionate research in neuroscience; the research area of non-neuronal cells is bright. References: Absinta; M.; Maric; D.; Gharagozloo; M.; Garton; T.; Smith; M.D.; Jin; J.; et al. (2021). A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature. Ajami; B.; Samusik; N.; Wieghofer; P.; Ho; P.P.; Crotti; A.; Bjornson; Z.; et al. (2018). Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci 21; 541-551. Auguste; Y.S.S.; Ferro; A.; Kahng; J.A.; Xavier; A.M.; Dixon; J.R.; Vrudhula; U.; et al. (2022).Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice. Nat Neurosci 25; 1273-1278. Badimon; A.; Strasburger; H.J.; Ayata; P.; Chen; X.; Nair; A.; Ikegami; A.; et al. (2020). Negative feedback control of neuronal activity by microglia. Nature 586; 417-423. Bergles; D.E.; Roberts; J.D.; Somogyi; P.; and Jahr; C.E. (2000). Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405; [187][188][189][190][191]
Keywords:
glia
astrocytes
microglia
OPC
oligodendrocyte
non-neuronal cells
border cells
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