Morgan, Sarah Claire; (2002) Microglial-neuronal interactions pertinent to neuronal development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Microglia, the resident macrophage of the brain, were originally assumed to merely provide structural support for the surrounding neurones, however it is now accepted that microglia play more than a passive role during embryonic development and neural injury, for example in Alzheimer's Disease, multiple sclerosis, and AIDS associated dementia, but it is still unclear whether microglia aid neuronal survival or exacerbate neuronal death. Microglia are implicated in a variety of cellular functions including release of cytokines and cytotoxins, phagocytosing cellular debris and synaptic stripping, all of which can influence neuronal development, differentiation and survival. Such differential microglial responses may well depend on the signals received from the surrounding microenvironment. In these studies the effect of microglia on the survival of cultured cerebellar granule neurones (CGCs) have been investigated. Conditioned medium (MG-CM) collected from primary microglial cultures, at either 1 day in vitro or 7 days in vitro, was used to treat 7 day in vitro neurones and neuronal cell viability was assessed over the following 7 days. MG-CM enhanced the CGC survival compared with untreated CGCs, with the 7 day in vitro MG-CM enhancing survival by up to 80% above control levels. Addition of conditioned medium obtained from cultures where the microglia had been selectively depleted using L-leucine methyl ester removed this effect to produce control levels of CGC survival. Neuronal expression of the nuclear antigen Ki-67 was seen to be amplified following treatment with the MG-CM, compared with control, suggesting a proliferation of neuronal precursor cells. These results show that microglia aged in culture are not only able to promote neuronal survival but also enhance neuronal precursor cell proliferation through the release of a microglial-derived neurotrophic factor. These results have ramifications for increasing the neuronal number in the developing or damaged brain through the modulation of neurotrophic factors.

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