Pathological dynamics of activated microglia following medial forebrain bundle transection

To elucidate the role and pathological dynamics of activated microglia, this study assessed the phagocytic, immunophenotypic, morphological, and migratory properties of activated microglia in the medial forebrain bundle (MFB) axotomized rat brain. Activated microglia were identified using two different monoclonal antibodies: ED1 for phagocytic activity and OX6 for major histocompatibility complex (MHC) class II. Phagocytic microglia, characterized by ED1-immunoreactivity or ED1- and OX6-immunoreactivity, appeared in the MFB and substantia nigra (SN) as early as 1-3 days post-lesion (dpl), when there was no apparent loss of SN dopamine (DA) neurons. Thereafter, a great number of activated microglia selectively adhered to degenerating axons, dendrites and DA neuronal somas of the SN. This was followed by significant loss of these fibers and nigral DA neurons. Activation of microglia into phagocytic stage was most pronounced between 14 approximately 28 dpl and gradually subsided, but phagocytic microglia persisted until 70 dpl, the last time point examined. ED1 expression preceded MHC II expression in phagocytic microglia. All phagocytic microglia sticking to DA neurons showed activated but ramified form with enlarged somas and thickened processes. They were recruited to the SNc from cranial, dorsal and ventral aspects along various structures and finally stuck to DA neurons of the SNc. Characteristic rod-shaped microglia in the white matter were thought to migrate a long distance. The present study strongly suggests that neurons undergoing delayed neurodegeneration may be phagocytosed by numerous phagocytic, ramified microglia at various sites where specific surface signals are exposed or diffusible molecules are released.