Objective: We aim to explore the role of glial cells in Parkinson’s disease and assess whether modulating microgliafunction could offer therapeutic benefits. Specifically, we investigate if a treatment that inhibits microglialreactivity can prevent the synaptic pruning observed in animal models of the disease.

Background: In Parkinson’s disease, the loss of dopaminergic innervation of the striatum leads to synaptic spine pruning of medium spiny neuron (MSNs) dendritic arbors. Animal models show that spine loss differentially affects direct and indirect pathway MSNs.

Microglia, immune cells of the central nervous system, become activated during inflammation linked to neurodegeneration, and may exacerbate their phagocytic capacity. While microglia involvement in promoting dopaminergic neuron loss is known, their role in the synaptic plasticity of the striatum due to dopaminergic denervation remains unexplored.

Method: Using female adult D1-Tomato mice, we induced a hemi-parkinsonism model by injecting the toxin 6-OHDA into the left medial forebrain bundle. Subsequently, mice received doxycycline in the drinking water for five weeks to inhibit microglial reactivity. Tissue was then processed for immunohistochemical analysis, images were acquired using structured illumination fluorescence microscopy and dendritic spine density of MSNs was quantified.

Results: Our findings replicated the reduction in dendritic spine density observed in MSNs from both the direct and indirect pathways of parkinsonian animals, compared to sham-lesioned controls. Doxycycline produced a significant decrease of dendritic spine density in MSNs from the indirect pathway both in parkinsonian and control mice. Interestingly, dendritic spine density was differentially affected by doxycycline in MSNs from parkinsonian and control mice (significant interaction in 2-way ANOVA with lesion and drug as factors). However, this effect was not robust enough to be detected by post-hoc comparisons.

Conclusion: While our findings corroborate previous research showing reduced dendritic spine density in MSNs of parkinsonian animals, we require more statistical power to confirm a protective effect of doxycycline treatment on synaptic spine loss by MSNs of the direct pathway. Further research is needed to clarify the role of microglia and therapeutic potential of its modulation in Parkinson’s pathophysiology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-the-therapeutic-potential-of-microglial-modulation-in-parkinsons-disease-a-study-on-structural-synaptic-plasticity/