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

• Published in: Neuropharmacology Vol. 73; pp. 192 - 203
• Main Authors: Workman, E.R., Niere, Farr, Raab-Graham, Kimberly F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2013
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Antagonists; Baclofen - pharmacology; Brain-Derived Neurotrophic Factor - metabolism; Calcium - metabolism; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - metabolism; Calcium imaging; Cells, Cultured; Cytoskeletal Proteins - metabolism; Excitatory Amino Acid Antagonists - pharmacology; GABA Antagonists - pharmacology; GABA-B Receptor Agonists - pharmacology; GABAB receptors; Hippocampal neurons; Hippocampus - metabolism; Humans; Immobility Response, Tonic - drug effects; L-type calcium channels; Male; Mechanistic Target of Rapamycin Complex 1; Mice; mTORC1; Multiprotein Complexes - metabolism; Nerve Tissue Proteins - metabolism; NMDA receptors; Organophosphorus Compounds - pharmacology; Piperidines - pharmacology; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Primary Cell Culture; Protein synthesis; Rapid antidepressant; Receptors, AMPA - metabolism; Receptors, GABA-B - metabolism; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - metabolism; Hippocampal neurons; GABAB receptors; Protein synthesis; L-type calcium channels; Rapid antidepressant; Calcium imaging; Prefrontal cortex; NMDA receptors; mTORC1; GABA(B) receptors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.05.037

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. •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.