Deletion of Atf6 alpha enhances kainate-induced neuronal death in mice

作者：Kezuka Dai; Tkarada Iemata Mika; Hattori Tsuyoshi; Mori Kazutoshi; Takahashi Ryosuke; Kitao Yasuko; Hori Osamu^*

来源：Neurochemistry International, 2016, 92: 67-74.

DOI：10.1016/j.neuint.2015.12.009

• ATF6 alpha
• Kainate
• Neuronal death
• UPR
• Ca2+

Excessive amount of L-glutamate in the brain causes neuronal damage in various pathological conditions including epilepsy and stroke. We previously reported that the 150-kDa oxygen-regulated protein (ORP150), a molecular chaperone in the endoplasmic reticulum (ER), inhibited the L-glutamate-induced neuronal death, at least partly, by improving Ca2+ homeostasis in the ER. In the present study, we analyzed the role of activating transcription factor 6 alpha. (ATF6 alpha), an upstream transcriptional factor critical for the operation of the ER, using mouse intrahippocampal kainate (KA) injection model. Expression of Hspa5, which encodes the molecular chaperone 78 kDa glucose-regulated protein (GRP78), increased after KA injection in the wild type (WT) mice. Comparative analysis using WT and Atf6 alpha(-/-) mice revealed that MA induced pronounced neuronal death in the CA3 region of Atf6 alpha(-/-) mice. The enhanced neuronal death in Atf6 alpha(-/-) mice was associated with reduced expression of molecular chaperones in the ER and significant induction of c-fos in the hippocampal neurons. Furthermore, an injection of dantrolene, an inhibitor of ryanodine receptor, partially rescued these effects in Atf6 alpha(-/-) mice after KA injection. Our results suggest that ATF6 alpha plays an important role in neuronal survival after KA-induced excitotoxicity through the regulation of Ca2+ response and neuronal activity.

• 出版日期2016-1