Time course of proliferation and elimination of microglia/macrophages in different neurodegenerative conditions.

Ablation of the hindlimb area of the sensorimotor cortex produces degeneration in the cortex (invasive traumatic injury) and leads to retrograde and/or anterograde degeneration in the thalamus (non-invasive injury, distal reaction). This provides an useful model to study the proliferation and elimination of microglia/macrophages in different neurodegenerative conditions. Changes in the morphology, distribution and numbers of microglia in the affected cortex and thalamus were analyzed at various time points (12 h to 30 days) after injury. In parallel, proliferation was determined by immunocytochemistry for the proliferating cell nuclear antigen and cell death by the TUNEL method. Proliferation was an early event in the microglia/macrophage response (from 12 h in the cortex and from 2 days post-lesion in the thalamus) and persisted up to 30 days. The different microglia/macrophage phenotypes proliferated in a specific temporospatial pattern. In the lesioned cortex, early activation and proliferation of intrinsic microglia was accompanied, from the second post-lesion day, by monocyte entrance and proliferation of monocyte-derived cells. In contrast, accumulation of cells in the thalamus resulted from proliferation of intrinsic microglia, without apparent/significant monocytic recruitment. During the subsequent microglia/macrophages removal the majority of the cells in the cortex transformed into ameboid cells devoid of cell processes that progressively accumulated as fully-developed macrophages tissue within the lesion (3-14 days) ultimately migrating out to the meningeal connective tissue (14-30 days). Only some process-bearing cells, remaining in the cortical tissue bordering the lesion, underwent degeneration by 14-21 days post-lesion. In contrast, in the distal affected thalamic nuclei, microglial cell death occurred by 14-30 days post-lesion. Altogether, this study shows that both the origin and fate of microglia/macrophages depend on the nature of the lesion.