The effects of astrocytes on differentiation of neural stem cells are influenced by knock-down of the glutamate transporter, GLT-1

The majority of glutamate released during neurotransmission is uptaken into astrocytes through the glial glutamate transporter GLT-1, by which extracellular glutamate is inactivated. In this study, we determined whether GLT-1 mediated the astrocyte regulation of the cell fate of neural stem/progenitor cells (NSCs) by glutamate reuptake. The astrocytes stimulated neuronal lineage selection but inhibited glial lineage cells. However, all these effects were reversed after siRNA-targeting GLT-1 was delivered into astrocytes by lentiviral vectors. NSC and astrocyte co-culture also increased the synaptophysin protein levels of NSC-derived new neurons through GLT-1. Glutamate was found to be present in the supernatants of the co-culture and astrocytes under different medium conditions, which may be attributed to the slower rate of clearance of the released glutamate. Dysfunctional glutamate reuptake may be the major consequence of GLT-1 functional silence in astrocytes. These results indicated that astrocytes regulated NSCs in reactive astrogliosis, neuronal generation, and synaptic function through GLT-1.