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Microglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity
Caitlin Castagnola1,2, Roberta Marongiu3, Yuansong Wan1
1Helen and Robert Appel Institute for Alzheimer's Disease Research, Brain and Mind Research Institute, Weill Cornell Medicine; New York, NY, USA.
Abstract:
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 hippocampal 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.
Insights
Microglia protect against levodopa-induced dyskinesia (LID) by acting as a brake on maladaptive brain plasticity. Soluble TREM2 (sTREM2) enhances this protective pathway, offering therapeutic potential for Parkinson's disease complications.
Area of Science:
- Neuroimmunology
- Neuroplasticity
- Parkinson's Disease Research
Background:
- Microglia, the brain's immune cells, continuously monitor neural activity, but their role in experience-dependent synaptic plasticity remains largely unknown.
- Levodopa-induced dyskinesia (LID), a severe complication of Parkinson's disease (PD), is associated with maladaptive changes in the striatum and often attributed to neuroinflammation.
Purpose of the Study:
- To investigate the role of microglia in levodopa-induced dyskinesia (LID) and explore potential therapeutic strategies targeting microglial function.
- To elucidate the molecular mechanisms by which microglia modulate synaptic plasticity and striatal remodeling in the context of LID.
Main Methods:
- Single-nucleus transcriptomics to analyze microglial gene programs and neuronal remodeling in PD patients and mouse models.
- Experimental manipulation of microglial populations (depletion and repopulation) and delivery of adeno-associated virus (AAV) expressing soluble TREM2 (sTREM2).
- Assessment of LID severity, synaptic plasticity, and neuronal excitability in response to microglial interventions and sTREM2 treatment.
Main Results:
- A specific microglial gene program associated with dyskinesia was identified in PD patients.
- Microglial depletion worsened LID, while repopulation or sTREM2 treatment significantly mitigated LID without compromising levodopa's therapeutic effects.
- Microglial loss induced widespread transcriptional remodeling in spiny projection neurons (SPNs), which was reversed by microglial repopulation or sTREM2.
- sTREM2 was found to directly engage TrkB, potentiating BDNF-dependent signaling and enhancing synaptic plasticity.
Conclusions:
- Microglia act as a crucial protective brake against maladaptive striatal plasticity underlying LID.
- The neuroimmune pathway involving soluble TREM2 (sTREM2) and TrkB signaling represents a novel therapeutic target for managing LID in Parkinson's disease.
- Modulating microglial function via sTREM2 offers a promising strategy to rebalance striatal circuit function and alleviate LID symptoms.
