<STRONG STYLE="">PHARMACOLOGICAL TARGETING OF MICROGLIAL REACTIVITY IN PRECLINICAL MODEL OF PARKINSON´S DISEASE</STRONG>

Parkinson’s disease is associated with circuit remodeling driven by maladaptive structural plasticity. We investigated the cellular and behavioral correlates of pathological plasticity in an experimental 6-OHDA mouse model of Parkinson’s disease, focusing on synaptic alterations and microglia as a therapeutic target.
Pharmacological inhibition of microglial reactivity with doxycycline was applied to examine whether modulation of glial activity impacts synaptic and behavioral outcomes. Structural plasticity was assessed using high-resolution fluorescence microscopy combined with quantitative image analysis of dendritic spines, including spine density and subtype composition as readouts of synaptic remodeling. Microglial responses were characterized across disease stages and experimental conditions by integrated measurements of cell density, morphological state, phagocytic activity, and contact frequency with neuronal elements. In parallel, spontaneous motor behavior was evaluated in exploratory paradigms.
Dopaminergic denervation induced robust synaptic alterations, including striatal reductions in spine density and a shift in spine subtype distribution toward enrichment in stable spines. These synaptic changes were accompanied by marked microglial remodeling, including reactive morphology, increased phagocytosis, and enhanced microglia–neuron interactions. Pharmacological attenuation of microglial reactivity partially normalized striatal spine density, together with reductions in phagocytic activity and microglia–neuron contact frequency. However, despite these structural improvements, treated animals did not exhibit detectable recovery of motor behavior, as assessed by conventional and machine-learning–based analyses.
Together, these findings indicate that microglial modulation can influence disease-related synaptic plasticity in Parkinson’s disease, while also highlighting a dissociation between structural synaptic recovery and behavioral outcome, with implications for therapeutic strategies targeting glial function.