Summary
This study investigates the re-emergence of T cell-mediated synaptic dysfunction during the transition from relapsing-remitting to secondary progressive multiple sclerosis using a chimeric experimental model. The authors demonstrate that T cells from SPMS patients increase excitatory synaptic transmission in murine brain slices—mimicking the synaptotoxic effect previously observed in active RRMS stages—and that siponimod, an S1P receptor modulator, reverses this effect through S1P5R activation. These findings suggest that inflammatory-mediated synaptic dysfunction represents a tractable pathological mechanism underlying MS progression.
Regional applicability
This is a basic research study using in vitro models and does not directly address United Kingdom clinical practice or policy. However, the findings are relevant to UK neurology as they support the mechanistic rationale for S1PR modulator treatment (siponimod) in progressive MS, which is already licensed for clinical use. The results may inform patient stratification and treatment optimisation in UK MS services, though clinical validation in prospective patient cohorts would be required.
Key measures
Spontaneous glutamatergic synaptic transmission in striatal neurons (number of synapses analysed); T cell-induced excitatory synaptic activity; S1P receptor involvement in siponimod-mediated synaptic recovery
Outcomes reported
The study measured striatal excitatory synaptic transmission in chimeric experiments using human T cells incubated on murine brain slices, and assessed the effects of siponimod treatment on T cell-induced synaptotoxicity. Results showed that SPMS patient-derived T cells significantly increased glutamatergic activity compared to healthy controls, and that siponimod treatment rescued this synaptotoxic effect.
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