Pathological Dynamics of Activated Microglia Following Medial Forebrain Bundle Transection

Abstract

KEY WORDS axotomy; phagocytosis; ED1; MHC II; migration; dopami- nergic neuron; Parkinson’s disease

To elucidate the role and pathological dynamics of activated microglia, this study assessed the phagocytic, immunopheno- typic, morphological, and migratory properties of activated microglia in the medial forebrain bundle (MFB) axotomized rat brain. Activated microglia were identified using two dif- ferent monoclonal antibodies: ED1 for phagocytic activity and OX6 for major histocompatibility complex (MHC) class II. Phagocytic microglia, characterized by ED1-immuno- reactivity 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 acti- vated microglia selectively adhered to degenerating axons, dendrites and DA neuronal somas of the SN. This was fol- lowed by significant loss of these fibers and nigral DA neu- rons. Activation of microglia into phagocytic stage was most pronounced between 1428 dpl and gradually subsided, but phagocytic microglia persisted until 70 dpl, the last time point examined. ED1 expression preceded MHC II expres- sion in phagocytic microglia. All phagocytic microglia stick- ing to DA neurons showed activated but ramified form with enlarged somas and thickened processes. They were re- cruited 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 phago- cytic, ramified microglia at various sites where specific sur- face signals are exposed or diffusible molecules are released. V V C 2005 Wiley-Liss, Inc