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Mechanism of microglia neuroprotection: Involvement of P2X7, TNFα, and valproic acid

Recently, we have demonstrated that ramified microglia are neuroprotective in N‐methyl‐d‐aspartate (NMDA)‐induced excitotoxicity in organotypic hippocampal slice cultures (OHSCs). The present study aimed to elucidate the underlying neuron‐glia communication mechanism. It is shown here that pretreatment of OHSC with high concentrations of adenosine 5′‐triphosphate (ATP) reduced NMDA‐induced neuronal death only in presence of microglia. Specific agonists and antagonists identified the P2X7 receptor as neuroprotective receptor which was confirmed by absence of ATP‐dependent neuroprotection in P2X7‐deficient OHSC. Microglia replenished chimeric OHSC consisting of wild‐type tissue replenished with P2X7‐deficient microglia confirmed the involvement of microglial P2X7 receptor in neuroprotection. Stimulation of P2X7 in primary microglia induced tumor necrosis factor α (TNFα) release and blocking TNFα by a neutralizing antibody in OHSC abolished neuroprotection by ATP. OHSC from TNFα‐deficient mice show increased exicitoxicity and activation of P2X7 did not rescue neuronal survival in the absence of TNFα. The neuroprotective effect of valproic acid (VPA) was strictly dependent on the presence of microglia and was mediated by upregulation of P2X7 in the cells. The present study demonstrates that microglia‐mediated neuroprotection depends on ATP‐activated purine receptor P2X7 and induction of TNFα release. This neuroprotective pathway was strengthened by VPA elucidating a novel mechanism for the neuroprotective function of VPA. GLIA 2016;64:76–89