BRAIN MICROGLIA MACROPHAGES EXPRESS NEUROTROPHINS THAT SELECTIVELY REGULATE MICROGLIAL PROLIFERATION AND FUNCTION

Although microglia-mediated cytotoxicity has been extensively investig ated, little is known about the potential microglial role in neuronal and glial support. Characterization of trophin elaboration by microgli a and identification of responsive populations may define novel functi ons. We now report that microglia/brain macrophages express neurotroph ins of the nerve growth factor (NGF) gene family in vitro and in vivo, suggesting that these cells promote development and normal function o f neurons and glia. Moreover, neurotrophins promote microglial prolife ration and phagocytic activity in vitro. We found that microglia expre ss neurotrophins in a region-specific manner and that within any regio n only subpopulations elaborate trophins. Using an antiserum specific for neurotrophin-3 (NT-3) with the microglial/macrophage marker OX-42 on postnatal day 10 in vivo, double-labeled cells were identified in t he cerebral cortex, globus pallidus, and medulla; NT-3 was undetectabl e in OX-42-positive cells in the ependyma, the external capsule, choro id plexus, and meninges. In contrast, ramified microglia in the adult brain did not exhibit NT-3 immunoreactivity, suggesting developmental regulation of microglial NT-3 expression. In situ hybridization studie s on purified microglial cultures confirmed that only subpopulations e xpress the NGF and NT-3 genes, substantiating the existence of microgl ial heterogeneity. We tentatively conclude that microglial subtypes se rve trophic roles in the normal brain, in addition to exerting well do cumented deleterious actions in illness and injury. Microglia were als o responsive to neurotrophins: brain-derived neurotrophic factor (BDNF ) and NT-3 increased [H-3]thymidine incorporation in vitro, and NT-3 p romoted proliferation. Moreover, NT-3 induced phagocytic activity, sug gesting that the factor plays a role in processes associated with cell ular activation.