51. Vascular endothelial growth factor receptor-3 regulates astroglial glutamate transporter-1 expression via mTOR activation in reactive astrocytes following pilocarpine-induced status epilepticus
- Author
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Mun-Yong Lee, Kyung-Ok Cho, Won Joo Kim, Kyoung Hoon Jeong, and Seong Yun Kim
- Subjects
0301 basic medicine ,Vascular Endothelial Growth Factor A ,Amino Acid Transport System X-AG ,Hippocampus ,Status epilepticus ,Biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Status Epilepticus ,Downregulation and upregulation ,medicine ,Humans ,Receptor ,PI3K/AKT/mTOR pathway ,TOR Serine-Threonine Kinases ,Glutamate receptor ,Pilocarpine ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-3 ,Cell biology ,Astrogliosis ,Vascular endothelial growth factor ,030104 developmental biology ,Neurology ,chemistry ,Excitatory Amino Acid Transporter 2 ,Astrocytes ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Recent evidence has shown that the vascular endothelial growth factor (VEGF) system plays a crucial role in several neuropathological processes. We previously reported an upregulation of VEGF-C and its receptor, VEGFR-3, in reactive astrocytes after the onset of status epilepticus (SE). However, it remains unknown, which molecules act as downstream signals following VEGFR-3 upregulation, and are involved in reactive astrogliosis after SE. Therefore, we investigated whether VEGFR-3 upregulation within reactive astrocytes is associated with the activation of mammalian target of rapamycin (mTOR) signaling, which we confirmed by assaying for the phosphorylated form of S6 protein (pS6), and whether VEGFR-3-mediated mTOR activation induces astroglial glutamate transporter-1 (GLT-1) expression in the hippocampus after pilocarpine-induced SE. We found that spatiotemporal expression of pS6 was consistent with VEGFR-3 expression in the hippocampus after SE, and that both pS6 and VEGFR-3 were highly expressed in SE-induced reactive astrocytes. Treatment with the mTOR inhibitor rapamycin decreased astroglial VEGFR-3 expression and GLT-1 expression after SE. Treatment with a selective inhibitor for VEGFR-3 attenuated astroglial pS6 expression as well as suppressed GLT-1 expression and astroglial reactivity in the hippocampus after SE. These findings demonstrate that VEGFR-3-mediated mTOR activation could contribute to the regulation of GLT-1 expression in reactive astrocytes during the subacute phase of epilepsy. In conclusion, the present study suggests that VEGFR-3 upregulation in reactive astrocytes may play a role in preventing hyperexcitability induced by continued seizure activity.
- Published
- 2020