Changes in Neuronal Excitability by Activated Microglia: Differential Na(+) Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18

Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na(+) current densities (I(NavD)) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases I(NavD) below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated I(NavD) significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of I(NavD) in bipolar cells, whereas in pyramid-shaped cells, increases in I(NavD) were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on I(NavD) in both cell types. Exposure to 5–10 ng/ml IL-18 for 4 days increased I(NavD) in both pyramid-shaped as well as bipolar neurons, albeit the dose–response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na(+) current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of I(NavD) in response to TNF-α as well as respond to smaller concentrations of IL-18, our results offer an explanation for the finding, that in certain conditions of brain inflammations periods of dizziness are followed by epileptic seizures.