GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324025/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324025GEOGSEfalseMicroglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity.Microglia continuously survey the brain and shape neuronal activity, but their contribution to experience-dependent synaptic plasticity is unclear. Levodopa-induced dyskinesia (LID) is a disabling complication of late-stage Parkinson’s disease (PD) that is linked to maladaptive striatal remodeling and is often assumed to reflect detrimental neuroinflammation. Here we identify a dyskinesia-associated microglial gene program in the striatum of PD patients and show that microglia instead act as a protective brake on LID. In a mouse model, microglial depletion exacerbated dyskinesia, whereas microglial repopulation mitigated it. Delivery of AAV expressing soluble TREM2 (sTREM2) similarly reduced LID without impairing the therapeutic benefit of levodopa. Single-nucleus transcriptomics revealed that microglial loss drives extensive remodeling of both direct and indirect spiny projection neurons (SPNs), while repopulation or sTREM2 reverses a large fraction of LID-associated transcriptional changes. Mechanistically, sTREM2 directly engages TrkB and potentiates BDNF-dependent TrkB–ERK signaling, consistent with positive allosteric modulation. Functionally, sTREM2 enhances BDNF-TrkB-dependent hsciippocampal synaptic plasticity and acutely rebalances striatal dendritic excitability in a compartment- and cell type-specific manner. These findings reveal an unexpected neuroimmune pathway in which microglia restrain maladaptive plasticity via sTREM2–TrkB signaling, with therapeutic implications.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 musculus[42146496]