mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling

- GABAB receptors activate mTORC1 activity when NMDA receptors are blocked.
- GABABRs increase dendritic calcium levels by coupling to L-type calcium channels.
- Blocking GABABRs in vivo occludes rapid antidepressant effect.
- GABABR is required for mTORC1-mediated translation with rapid antidepressants.

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 γ-amino-butyric acid B receptors (GABABR) facilitate dendritic calcium entry. The GABABR-mediated increase in calcium signal requires the availability of dendritic L-type calcium channels. Moreover, GABABR can activate mTOR and increase mTOR dependent expression of BDNF under the same NMDAR blocked conditions. In vivo, blocking GABABR 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 GABABRs in the antidepressant action of NR2B antagonists and as an initiator/regulator of mTORC1-mediated translation.