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Neuropharmacology. 2013 Oct;73:192-203. doi: 10.1016/j.neuropharm.2013.05.037. Epub 2013 Jun 8.

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

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Center for Learning and Memory, Section of Neurobiology, University of Texas at Austin, Austin, TX 78712, USA.


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.


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

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