Neuroinflammation and Synaptic Plasticity in Multiple Sclerosis

Multiple sclerosis (MS) is characterised by an autoimmune attack on the central nervous system, leading to demyelination, axonal damage and a persistent neuroinflammatory milieu. Resident glial cells, especially microglia and astrocytes, release a spectrum of pro-inflammatory cytokines that disrupt the balance of synaptic strength and plasticity. Under physiological conditions, synaptic plasticity mechanisms such as long-term potentiation and homeostatic scaling underlie learning and functional compensation. In MS, however, excessive release of molecules like tumour necrosis factor (TNF) and interleukin-1β (IL-1β) drives excitotoxicity, impairs inhibitory circuits and reduces synaptic resilience. This inflammatory synaptopathy contributes to motor and cognitive deficits throughout disease stages and underpins the transition from relapsing–remitting to progressive forms. Therapeutic strategies targeting specific cytokine pathways, glial activation states and ionic receptor modulators have begun to restore synaptic homeostasis and protect neuronal networks. Rapid advances in our understanding of how immune mediators sculpt synaptic environments are opening avenues for precision therapies aimed at preserving plasticity in people with MS.

Research from Nature Portfolio

Recent studies have interrogated genetic and microglial determinants of synaptic dysfunction in MS. A case–control analysis of a common IL-13 gene polymorphism revealed that carriers of the variant allele exhibit increased susceptibility to MS, suggesting that altered cytokine signalling can prime the CNS for exaggerated inflammatory responses. Complementing this, foundational work in an animal model demonstrated that hippocampal microglia remain persistently activated after motor symptom remission, driving long-term potentiation deficits via the NADPH oxidase complex. Inhibition of this enzyme restored synaptic plasticity and spatial memory performance, underscoring oxidative microglial mechanisms as key modulators of cognitive resilience in MS.

Neuroinflammation and Synaptic Plasticity in Multiple Sclerosis publication trend

The graph below shows the total number of articles in neuroinflammation and synaptic plasticity in multiple sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Neuroinflammation: A sustained inflammatory response within the central nervous system involving glial activation and cytokine release.

Synaptic plasticity: The ability of synapses to strengthen or weaken over time in response to activity or environmental changes.

Microglia: Resident immune-competent cells of the CNS that mediate inflammatory and homeostatic functions.

Cytokine: A signalling protein secreted by immune or glial cells that modulates inflammatory and cellular responses.

Excitotoxicity: Neuronal damage caused by excessive glutamate receptor activation leading to calcium overload.

Inflammasome: A multiprotein complex in innate immune cells that activates inflammatory cytokines such as IL-1β.

Synaptopathy: Pathological alteration of synaptic structure or function contributing to neurological deficits.

Sphingosine 1-phosphate receptor (S1PR): A cell-surface receptor that modulates lymphocyte trafficking and neural signalling, targeted by disease-modifying agents.

References

1. Multiple sclerosis susceptibility may be associated with the coding rs20541 (R130Q) IL-13 gene polymorphism in the Polish population. Scientific Reports (2023).
2. Persistent activation of microglia and NADPH oxidase drive hippocampal dysfunction in experimental multiple sclerosis. Scientific Reports (2016).
3. Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis. Journal of Neuroinflammation (2024).
4. Re-emergence of T lymphocyte-mediated synaptopathy in progressive multiple sclerosis. Frontiers in Immunology (2024).
5. Inhibiting the NLRP3 Inflammasome with MCC950 Alleviates Neurological Impairment in the Brain of EAE Mice. Molecular Neurobiology (2023).
6. Tumor Necrosis Factor and Interleukin‐1β Modulate Synaptic Plasticity during Neuroinflammation. Neural Plasticity (2018).
7. Inflammation Subverts Hippocampal Synaptic Plasticity in Experimental Multiple Sclerosis. PLOS ONE (2013).