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

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

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.

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

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Baclofen / pharmacology
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Calcium / metabolism
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism*
  • Excitatory Amino Acid Antagonists / pharmacology
  • GABA Antagonists / pharmacology
  • GABA-B Receptor Agonists / pharmacology
  • Hippocampus / metabolism
  • Humans
  • Immobility Response, Tonic / drug effects
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism*
  • Nerve Tissue Proteins / metabolism*
  • Organophosphorus Compounds / pharmacology
  • Piperidines / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Primary Cell Culture
  • Receptors, AMPA / metabolism
  • Receptors, GABA-B / metabolism*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Brain-Derived Neurotrophic Factor
  • Calcium Channels, L-Type
  • Cytoskeletal Proteins
  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • GABA-B Receptor Agonists
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Organophosphorus Compounds
  • Piperidines
  • Receptors, AMPA
  • Receptors, GABA-B
  • Ro-25-6891
  • activity regulated cytoskeletal-associated protein
  • 2-Amino-5-phosphonovalerate
  • CGP 35348
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Baclofen
  • Calcium
  • glutamate receptor ionotropic, AMPA 1