title: mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling.
abstract: 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.
authors.affiliation: Center for Learning and Memory, Section of Neurobiology, University of Texas at Austin, Austin, TX 78712, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Workman
authors.forename: Farr
authors.initials: F
authors.lastname: Niere
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Raab-Graham
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D018091:Receptors, AMPA / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015763:2-Amino-5-phosphonovalerate; D001418:Baclofen; D019208:Brain-Derived Neurotrophic Factor; D002118:Calcium; D020746:Calcium Channels, L-Type; D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009943:Organophosphorus Compounds; D010880:Piperidines; D018091:Receptors, AMPA; D018080:Receptors, GABA-B; D058570:TOR Serine-Threonine Kinases; C588224:Ro-25-6891; C092069:activity regulated cytoskeletal-associated protein; C066430:CGP 35348
keywords: Calcium imaging; GABA(B) receptors; Hippocampal neurons; L-type calcium channels; NMDA receptors; Prefrontal cortex; Protein synthesis; Rapid antidepressant; mTORC1