Glutamate induces neurotrophic factor production from microglia via protein kinase C pathway

Microglia are intrinsic immune cells in the central nervous system and play key roles in the pathogenesis of various central nervous system disorders. Microglia have been shown to attack damaged neurons by secreting a variety of neurotoxic factors including inflammatory cytokines, reactive oxygen species and glutamate. On the other hand, they can produce neurotrophic factors (NTFs) which support neuronal survival and growth. However, the precise mechanism that regulates microglial NTF production is not fully understood, and the relation between glutamate and NTFs remains unclear. In the present study, we show that glutamate significantly induces microglial NTF production by the activation of N-methyl-d-aspartate (NMDA) receptors, group III metabotropic glutamate receptors, and glutamate transporters. Activation of NMDA receptors and group III metabotropic glutamate receptors induces intracellular Ca2+ release from the endoplasmic reticulum. Further, stimulation of glutamate transporters leads to influx of extracellular Ca2+ in a Na+-dependent manner. This intracellular Ca2+ elevation activates the protein kinase C pathway which induces microglial NTF expression and production. These results suggest that microglia play a neuroprotective role during the excitotoxic state in neurodegenerative diseases.