Microglial cells (CNS’ macrophages) detect homeostatic imbalances of external and/or internal etiology and react by secreting proinflammatory cytokines, thereby orchestrating inflammation. The association between neuroinflammation and neurodegeneration suggests that proinflammatory cytokines might induce and/or enhance neuronal damage.

We investigated the neurotoxic impact of microglial activation in vitro using organotypic hippocampal slice cultures and chronic exposure to substances imitating either direct microglial activation by external factors (endotoxin) or secondary activation by glutamatergic excitotoxic neuronal death.

Microglial activation and inflammatory response were characterized by morphology (number, size and branching pattern) and titer of proinflammatory cytokines (IL1b, IL-6, TNFα) in the culture supernatant. Neuronal survival and function were assessed by means of morphology (Nissl staining, Fluoro-Jade^® B) and extracellular electrophysiology.

Endotoxin and excitotoxicity both induced microglial population expansion and morphological changes consistent with activation (process retraction, somatic enlargement). In spite of morphological similarity, microglia exhibited different profiles in proinflammatory cytokine secretion and association with neurodegeneration.

Endotoxin triggered massive secretion of proinflammatory cytokines (TNFα, IL6) without any evidence of neurodegeneration and with only minor effects on neuronal function, as demonstrated by the amplitude of neuronal responses and short-term plasticity properties.

Excitotoxicity, on the other hand, exhibited massive neuronal death with atypical microglial activation that did not elevate IL1b, IL6 and TNFα above the control level.

Concluding, microglia are differentially activated by endotoxin and excitotoxicity and the secretion of proinflammatory cytokines does not necessarily correlate with neuronal death or dysfunction.