Cited by 120Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersTreatment of Major Depression

Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation of GluA1-containing calcium-permeable AMPA receptors

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Fortin, D. A., Srivastava, T., Dwarakanath, D., Pierre, P., Nygaard, S., Derkach, V. A., Soderling, T. R.·2012·Journal of Neuroscience

Abstract

Glutamatergic synapses in early postnatal development transiently express calcium-permeable AMPA receptors (CP-AMPARs). Although these GluA2-lacking receptors are essential and are elevated in response to brain-derived neurotrophic factor (BDNF), little is known regarding molecular mechanisms that govern their expression and synaptic insertion. Here we show that BDNF-induced GluA1 translation in rat primary hippocampal neurons requires the activation of mammalian target of rapamycin (mTOR) via calcium calmodulin-dependent protein kinase kinase (CaMKK). Specifically, BDNF-mediated phosphorylation of threonine 308 (T308) in AKT, a known substrate of CaMKK and an upstream activator of mTOR-dependent translation, was prevented by (1) pharmacological inhibition of CaMKK with STO-609, (2) overexpression of a dominant-negative CaMKK, or (3) short hairpin-mediated knockdown of CaMKK. GluA1 surface expression induced by BDNF, as assessed by immunocytochemistry using an extracellular N-terminal GluA1 antibody or by surface biotinylation, was impaired following knockdown of CaMKK or treatment with STO-609. Activation of CaMKK by BDNF requires transient receptor potential canonical (TRPC) channels as SKF-96365, but not the NMDA receptor antagonist d-APV, prevented BDNF-induced GluA1 surface expression as well as phosphorylation of CaMKI, AKT(T308), and mTOR. Using siRNA we confirmed the involvement of TRPC5 and TRPC6 subunits in BDNF-induced AKT(T308) phosphorylation. The BDNF-induced increase in mEPSC was blocked by IEM-1460, a selected antagonist of CP-AMPARs, as well as by the specific repression of acute GluA1 translation via siRNA to GluA1 but not GluA2. Together these data support the conclusion that newly synthesized GluA1 subunits, induced by BDNF, are readily incorporated into synapses where they enhance the expression of CP-AMPARs and synaptic strength.

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Crossref · 10.1523/jneurosci.6034-11.2012

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  • BDNF increases AMPA responses by enhancing AMPA receptor translation and cell surface expression.

    “BDNF has been shown to increase α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses by enhancing AMPA receptor translation and cell surface expression (Caldeira et al., 2007; Fortin et al., 2012).”

    From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Fortin et al., 2012

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  1. Seeburg PH Higuchi M Sprengel R RNA editing of brain glutamate receptor channels: mechanism and physiology Brain Res Brain Res Rev 1998 26 217 229 9651532

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Authors
Fortin, D. A., Srivastava, T., Dwarakanath, D., Pierre, P., Nygaard, S., Derkach, V. A., & Soderling, T. R.
Affiliations
  • Oregon Health & Science University (US)
  • Aix-Marseille Université (FR)
Corresponding author
Fortin, D. A.
Venue
Journal of Neuroscience
Published
2012-06-13
Volume
32
Issue
24
Pages
8127-8137
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1965868120
Cited by
120
References
87
Citations by year
2026: 5 · 2025: 3 · 2024: 2 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 2 · 2018: 9 · 2017: 12 · 2016: 8 · 2015: 8 · 2014: 15 · 2013: 19 · 2012: 3
FWCI
5.93
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS027037, NS027037)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
brain-derived neurotrophic factor, calcium-permeable AMPA receptors, CaMKK, mTOR signaling, Akt phosphorylation, TRPC5, TRPC6, TRPC channels, glutamatergic synapses, hippocampal neurons, STO-609
MeSH terms
Adamantane, Animals, Benzimidazoles, Calcium Channel Blockers, Enzyme Inhibitors, Female, Hippocampus, Imidazoles, Male, Neurons, 2-Amino-5-phosphonovalerate, Rats, Sprague-Dawley, Receptors, AMPA, Excitatory Amino Acid Antagonists, Brain-Derived Neurotrophic Factor, RNA, Small Interfering, TRPC Cation Channels, Rats, Naphthalimides, Calcium-Calmodulin-Dependent Protein Kinase Kinase, Miniature Postsynaptic Potentials, Gene Knockdown Techniques, TOR Serine-Threonine Kinases, Primary Cell Culture

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