Mechanisms of microglia-mediated neuronal damage and dysfunction: Role of the "TNFa-Zn2+" cascade

• Applicant: Professor Dr. Heinz Beck
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2007 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33995431

The detailed role of microglia activation for impaired activity and damage of neuronal cells and networks after transient brain insults is unresolved. Recently, we observed insults such as status epilepticus (SE) to induce transient transcriptional upregulation of the Ca2+-channel Cav3.2 with concurrent increase in T-type Ca2+-current (/car) density and burst-firing, finally promoting neurodegeneration. Subsequently, we found that (a) activation of microglia augments Cav3.2 mRNA and (b) Zn2+ and TNFa are major factors for Cav3.2 promoter activation. We, therefore, hypothesize the following cascade: release of TNFa from activated microglia induces GluR1 insertion into the postsynaptic neuronal membrane => increased intracellular Zn2+ ([Zn2+]i) by influx via GluR1 containing AMPA receptors => Cav3.2 promoter activation => upregulation of Cav3.2 mRNA/protein => increased /car => neuronal hyperexcitability and degeneration. We will combine cell-, slice culture and in vivo experiments to (a) dissect this "TNFa-Zn2+ cascade, (b) analyze its endogenous recruitment by microglial TNFa, (c) examine the pathogenetic role of the "TNFa-Zn2+ cascade in models of cerebral insult and inflammation and (d) explore the potential to antagonize this pathomechanism.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 177: Innate Immunity in Chronic Neurodegeneration
• Participating Person: Professor Dr. Albert Becker