Objective To explore the regulating mechanism of the astrocytes on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) subunit in epileptogenesis. Methods The astrocytic conditional medium (ACM) was collected after being stimulated by glutamate, and then ACM was added to the cultured hippocampal neurons. The expression changes of neuronal GluR2 and protein interacting with C-kinase-1 (PICK1) mRNA were detected by RT-PCR. Results In the cultured hippocampal neurons, the GluR2 mRNA expression was significantly decreased at the 2nd, 8th, and 12th hours after the administration of ACM compared with that in the control group (P<0.05). However, the PICK1 mRNA expression was significantly increased at the same time points after the administration of ACM compared with that in the control group (P<0.05). The ionotropic glutamate receptor antagonists D-AP5 and CNQX could not fully block the action of ACM. Conclusion In epileptogenesis, the activation of astrocytes can downregulate the expression of neuronal AMPARs GluR2 subunit by upregul