mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABA(B)R signaling

作者：Workman E R; Niere Farr; Raab Graham Kimberly F^*

来源：Neuropharmacology, 2013, 73: 192-203.

DOI：10.1016/j.neuropharm.2013.05.037

• GABA(B) receptors
• NMDA receptors
• Protein synthesis
• Rapid antidepressant
• Hippocampal neurons
• Prefrontal cortex
• mTORC1
• L-type calcium channels
• Calcium imaging

Administration of N-methyl-D-aspartate receptors (NMDAR) antagonists initiates a rapid anti-depressant response requiring mammalian Target of Rapamycin Complex 1 (mTORC1) kinase; however the molecular mechanism is unknown. We have determined that upon NMDAR blockade, dendritic gamma-aminobutyric acid B receptors (GABA(B)R) facilitate dendritic calcium entry. The GABA(B)R-mediated increase in calcium signal requires the availability of dendritic L-type calcium channels. Moreover, GABA(B)R can activate mTOR and increase mTOR dependent expression of BDNF under the same NMDAR blocked conditions. In vivo, blocking GABA(B)R prevents the fast-acting, anti-depressant effect of the NR2B antagonist, Ro-25-6891, decreases active mTORC1 kinase, and reduces expression of BDNF and the AMPA receptor subunit GluA1. These findings propose a novel role for GABA(B)Rs in the antidepressant action of NR2B antagonists and as an initiator/regulator of mTORC1-mediated translation. Published by Elsevier Ltd.

• 出版日期2013-10