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

Dale A. Fortin, Taasin Srivastava, Diya Dwarakanath, Philippe Pierre, Sean Nygaard, Victor A. Derkach, Thomas Soderling

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    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 ofCaMKKand an upstream activator of mTOR-dependent translation, was prevented by (1) pharmacological inhibition ofCaMKKwith STO-609, (2) overexpression of a dominant-negativeCaMKK,or (3) short hairpin-mediated knockdown ofCaMKK.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 BDNFinduced GluA1 surface expression as well as phosphorylation of CaMKI,AKT T308, andmTOR.Using siRNAweconfirmed 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.

    Original languageEnglish (US)
    Pages (from-to)8127-8137
    Number of pages11
    JournalJournal of Neuroscience
    Volume32
    Issue number24
    DOIs
    StatePublished - Jun 13 2012

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    Transient Receptor Potential Channels
    AMPA Receptors
    Brain-Derived Neurotrophic Factor
    Phosphotransferases
    Calcium
    Threonine
    Calcium-Calmodulin-Dependent Protein Kinases
    1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
    Phosphorylation
    Sirolimus
    Synapses
    Calcium-Calmodulin-Dependent Protein Kinase Kinase
    Biotinylation
    N-Methyl-D-Aspartate Receptors
    Small Interfering RNA
    Immunohistochemistry
    Pharmacology
    Neurons
    Antibodies

    ASJC Scopus subject areas

    • Neuroscience(all)

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    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. / Fortin, Dale A.; Srivastava, Taasin; Dwarakanath, Diya; Pierre, Philippe; Nygaard, Sean; Derkach, Victor A.; Soderling, Thomas.

    In: Journal of Neuroscience, Vol. 32, No. 24, 13.06.2012, p. 8127-8137.

    Research output: Contribution to journalArticle

    Fortin, Dale A. ; Srivastava, Taasin ; Dwarakanath, Diya ; Pierre, Philippe ; Nygaard, Sean ; Derkach, Victor A. ; Soderling, Thomas. / 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. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 24. pp. 8127-8137.
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    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 ofCaMKKand an upstream activator of mTOR-dependent translation, was prevented by (1) pharmacological inhibition ofCaMKKwith STO-609, (2) overexpression of a dominant-negativeCaMKK,or (3) short hairpin-mediated knockdown ofCaMKK.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 BDNFinduced GluA1 surface expression as well as phosphorylation of CaMKI,AKT T308, andmTOR.Using siRNAweconfirmed 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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    AU - Srivastava, Taasin

    AU - Dwarakanath, Diya

    AU - Pierre, Philippe

    AU - Nygaard, Sean

    AU - Derkach, Victor A.

    AU - Soderling, Thomas

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