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.
Published by Elsevier Ltd.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Animals
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Baclofen / pharmacology
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Brain-Derived Neurotrophic Factor / metabolism*
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Calcium / metabolism
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Calcium Channels, L-Type / drug effects
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Calcium Channels, L-Type / metabolism
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Cells, Cultured
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Cytoskeletal Proteins / metabolism*
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Excitatory Amino Acid Antagonists / pharmacology
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GABA Antagonists / pharmacology
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GABA-B Receptor Agonists / pharmacology
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Hippocampus / metabolism
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Humans
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Immobility Response, Tonic / drug effects
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Multiprotein Complexes / metabolism*
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Nerve Tissue Proteins / metabolism*
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Organophosphorus Compounds / pharmacology
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Piperidines / pharmacology
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism
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Primary Cell Culture
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Receptors, AMPA / metabolism
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Receptors, GABA-B / metabolism*
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Brain-Derived Neurotrophic Factor
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Calcium Channels, L-Type
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Cytoskeletal Proteins
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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GABA-B Receptor Agonists
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Multiprotein Complexes
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Nerve Tissue Proteins
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Organophosphorus Compounds
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Piperidines
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Receptors, AMPA
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Receptors, GABA-B
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Ro-25-6891
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activity regulated cytoskeletal-associated protein
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2-Amino-5-phosphonovalerate
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CGP 35348
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Baclofen
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Calcium
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glutamate receptor ionotropic, AMPA 1