SYNAPTIC RELATIONSHIP BETWEEN MICROGLIA CELLS AND NEURONS THROUGHOUT THE DEGENERATIVE PROCESSES OF A MODEL OF SELECTIVE NEURONAL DEATH, THE PCD MUTANT MOUSE

The cerebellum coordinates motor behavior through organized and stable synaptic networks. Microglia is essential in synaptic pruning, formation and maturation. This study analyzes the Purkinje Cell Degeneration (PCD) mutant mouse, which exhibit selective and rapid Purkinje neuron loss and exacerbated microgliosis, in order to investigte how microglial inhibition with PLX5622 affects not only Purkinje cells survival but also microglial roles in synaptogenesis and pruning.
Synaptic organization was assessed at a pre-degenerative stage (P15) and peak degeneration (P25) by combining gene and protein expression of the excitatory postsynaptic marker PSD-95. Immunohistochemistry for Calbindin D28K, PSD-95 and Iba1, enabled a high-resolution quantification of Purkinje cells, excitatory synaptic puncta, microglial distribution and their spatial relationships. Colocalization analyses assessed synaptic density, microglial surveillance over neurons and synapses, and a possible microglial specialization.
At P15, we assessed mutation effects before Purkinje cell death; at P25, we evaluated PLX5622’s impact on synapses and neurodegeneration. Colocalization analysis showed that PLX5622 disrupted synaptic maturation under non-pathological conditions, confirming microglial involvement in synaptogenic refinement. Likewise, microglia overactivated by neuronal damage interferes with synaptic establishment even before the degeneration starts, presenting an apparent compensatory role. At P25, PLX5622-treated PCD mice showed surviving microglia selectively contacting synapses, suggesting a context-dependent neuroprotective or compensatory role. Ongoing work quantifies the fraction of microglial territory devoted to preserving these contacts in degenerative contexts.
This work demonstrates that PLX5622-driven microglial modulation exerts divergent, stage-dependent effects on synaptogenesis, revealing an early compensatory synaptic phase and a later microglia-dependent neuroprotective mechanism.