MORPHOLOGICAL AND IMMUNOPHENOTYPIC MICROGLIAL CHANGES IN THE DENERVATED FASCIA-DENTATA OF ADULT-RATS - CORRELATION WITH BLOOD-BRAIN-BARRIERDAMAGE AND ASTROGLIAL REACTIONS

The reactions of microglial and astroglial cells to anterograde axonal degeneration were studied in the fascia dentata of adult rats from 1 to 42 days after removal of the entorhinal perforant path projection. The observations focused on the kinetics of glial activation in terms of induction of immunomolecules on the glial cells and the possible co rrelation between these changes and lesion-induced extravasation of pl asma constituents. Normal and activated microglial cells were identifi ed by immunohistochemical visualization of the constitutively expresse d complement type 3 receptor (CR3/CD11b). Activated microglial cells w ere stained immunohistochemically for the inducible major histocompati bility complex (MHC) antigen class I and class II and the leukocyte co mmon antigen (LCA/ CD45). Astroglial cells were identified by immunohi stochemical staining for glial fibrillary acidic protein (GFAP). Blood -brain barrier (BBB) conditions were primarily evaluated by immunohist ochemical staining for extravasated Immunoglobulin G (IgG), but also b y intravenously injected horseradish peroxidase (HRP) and Evans Blue. Twenty-four hours after entorhinal cortex ablation, microglial cells i n the perforant path terminal zones displayed an increase in CR3 immun o-reactivity, changes of morphology and an induced expression of MHC a ntigen class I. At the same time there was a hitherto undescribed leak age of IgG through the BBB (albeit without detectable extravasation of HRP and Evans Blue). One day later microglial cells also expressed LC A, but MHC antigen class II was not induced under these degenerative c onditions, The activation of microglial cells occurred prior to a noti ceable hypertrophy of astroglial cells and increase in GFAP immunoreac tivity, as this first became evident on Postlesional Day 2. From the r esults we conclude (1) that perforant path axonal degeneration induces an endothelial transcytosis of blood-borne IgG by mechanisms which ca nnot be envisioned by conventional HRP tracer methods and (2) that the early activation of both microglial cells and astroglial cells is lik ely to be initiated and later influenced by both axonal degeneration a nd extravasated plasma constituents. The demonstration of an early ind uction of immunomolecules on activated microglial cells and extravasat ion of blood borne molecules might moreover form the basis for a corre spondingly early intervention aiming to regulate microglial immunomole cule, cytokine, and growth factor gene expression in the affected area s. (C) 1997 Academic Press