2007/03/03 by Margarida V. Caldeira, Margarida Caldeira, Carlos V. Melo +9 · 27 citations
Neuroscience · #Nerve injury and regeneration #Neurogenesis and neuroplasticity mechanisms #Neuropeptides and Animal Physiology
paper · pdf · doi:10.1074/jbc.m700607200
Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity in the hippocampus, but the mechanisms involved are not fully understood. The neurotrophin couples synaptic activation to changes in gene expression underlying long term potentiation and short term plasticity. Here we show that BDNF acutely up-regulates GluR1, GluR2, and GluR3 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits in 7-day tropomyosin-related kinase in vitro cultured hippocampal neurons. The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a Trk inhibitor, and by translation (emetine and anisomycin) and transcription (α-amanitine and actinomycin D) inhibitors. Accordingly, BDNF increased the mRNA levels for GluR1 and GluR2 subunits. Biotinylation studies showed that stimulation with BDNF for 30 min selectively increased the amount of GluR1 associated with the plasma membrane, and this effect was abrogated by emetine. Under the same conditions, BDNF induced GluR1 phosphorylation on Ser-831 through activation of protein kinase C and Ca2+-calmodulin-dependent protein kinase II. Chelation of endogenous extracellular BDNF with TrkB-IgG selectively decreased GluR1 protein levels in 14-day in vitro cultures of hippocampal neurons. Moreover, BDNF promoted synaptic delivery of homomeric GluR1 AMPA receptors in cultured organotypic slices, by a mechanism independent of NMDA receptor activation. Taken together, the results indicate that BDNF up-regulates the protein levels of AMPA receptor subunits in hippocampal neurons and induces the delivery of AMPA receptors to the synapse. Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity in the hippocampus, but the mechanisms involved are not fully understood. The neurotrophin couples synaptic activation to changes in gene expression underlying long term potentiation and short term plasticity. Here we show that BDNF acutely up-regulates GluR1, GluR2, and GluR3 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits in 7-day tropomyosin-related kinase in vitro cultured hippocampal neurons. The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a Trk inhibitor, and by translation (emetine and anisomycin) and transcription (α-amanitine and actinomycin D) inhibitors. Accordingly, BDNF increased the mRNA levels for GluR1 and GluR2 subunits. Biotinylation studies showed that stimulation with BDNF for 30 min selectively increased the amount of GluR1 associated with the plasma membrane, and this effect was abrogated by emetine. Under the same conditions, BDNF induced GluR1 phosphorylation on Ser-831 through activation of protein kinase C and Ca2+-calmodulin-dependent protein kinase II. Chelation of endogenous extracellular BDNF with TrkB-IgG selectively decreased GluR1 protein levels in 14-day in vitro cultures of hippocampal neurons. Moreover, BDNF promoted synaptic delivery of homomeric GluR1 AMPA receptors in cultured organotypic slices, by a mechanism independent of NMDA receptor activation. Taken together, the results indicate that BDNF up-regulates the protein levels of AMPA receptor subunits in hippocampal neurons and induces the delivery of AMPA receptors to the synapse. Neurotrophins are essential for the development of the vertebrate nervous system, modulate synaptic function, and play an important role in synaptic plasticity (1Poo M.M. Nat. Rev. Neurosci. 2001; 2: 24-32Crossref PubMed Scopus (1532) Google Scholar, 2Vicario-Abejon C. Owens D. McKay R. Segal M. Nat. Rev. Neurosci. 2002; 3: 965-974Crossref PubMed Scopus (205) Google Scholar). Brain-derived neurotrophic factor (BDNF) 3The abbreviations used are: BDNF, brain-derived neurotrophic factor; LTP, long term potentiation; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; DIV, days in vitro; CaMKII, Ca2+-calmodulin-dependent protein kinase II; GFP, green fluorescent protein; APV, dl-2-amino-5-phosphonovaleric acid; ANOVA, analysis of variance; PKC, protein kinase C; NMDA, N-methyl-d-aspartic acid; TrK, tropomyosin-related kinase. has been implicated in activity-dependent synaptic plasticity, particularly in long term potentiation (LTP) induced by high frequency stimulation. Accordingly, LTP is impaired in the hippocampal CA1 region of animals deficient in BDNF, but it can be rescued by supplying the neurotrophin (3Korte M. Carroll P. Wolf E. Brem G. Thoenen H. Bonhoeffer T. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8856-8860Crossref PubMed Scopus (1209) Google Scholar, 4Patterson S.L. Abel T. Deuel T.A.S. Martin K.C. Rose J.C. Kandel E.R. Neuron. 1996; 16: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (1038) Google Scholar, 5Korte M. Griesbeck O. Gravel C. Carroll P. Staiger V. Thoenen H. Bonhoeffer T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 12547-12552Crossref PubMed Scopus (308) Google Scholar). Chelation of endogenous BDNF also prevents the induction of LTP by theta burst stimulation and reduces late phase LTP induced by high frequency stimulation (6Figurov A. Pozzo-Miller L.D. Olafsson P. Wang T. Lu B. Nature. 1996; 381: 706-709Crossref PubMed Scopus (956) Google Scholar, 7Kang H. Welcher A.A. Shelton D. Schuman E.M. Neuron. 1997; 19: 653-664Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar). Furthermore, the late phase LTP induced by tetanic stimulation was not observed in slices from BDNF knock-out mice and was also abrogated when TrkB receptors were blocked (8Korte M. Kang H. Bonhoeffer T. Schuman E. Neuropharmacology. 1998; 37: 553-559Crossref PubMed Scopus (206) Google Scholar). Taken together, the available evidences point to a direct role of BDNF in the early and late phases of LTP. Binding of BDNF to TrkB receptors is followed by activation of intracellular signaling pathways, including the Ras/extracellular signal-regulated protein kinase, phospholipase Cγ (PLCγ), phosphatidylinositol-3-kinase/Akt, and Src pathways (9Narisawa-Saito M. Silva A.J. Yamaguchi T. Hayashi T. Yamamoto T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2461-2466Crossref PubMed Scopus (60) Google Scholar, 10Kaplan D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1670) Google Scholar, 11Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar). TrkB receptors are located on axon terminals and in the post-synaptic density of glutamatergic synapses (12Drake C.T. Milner T.A. Patterson S.L. J. Neurosci. 1999; 19: 8009-8026Crossref PubMed Google Scholar, 13Aoki C. Wu K. Elste A. Len G. Lin S. McAuliffe G. Black I.B. J. Neurosci. Res. 2000; 59: 454-463Crossref PubMed Scopus (97) Google Scholar, 14Pereira D.B. Rebola N. Rodrigues R.J. Cunha R.A. Carvalho A.P. Duarte C.B. J. Neurosci. Res. 2006; 83: 832-844Crossref PubMed Scopus (25) Google Scholar), but whether the effects of BDNF on synaptic plasticity are mediated by pre- and/or post-synaptic receptors is not fully elucidated. BDNF was originally shown to induce a long lasting potentiation of excitatory synaptic transmission in the hippocampal CA1 region, acting at a presynaptic site (15Kang H. Schuman E.M. 1995; PubMed Scopus Google results 4Patterson S.L. Abel T. Deuel T.A.S. Martin K.C. Rose J.C. Kandel E.R. Neuron. 1996; 16: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (1038) Google Scholar, A. Pozzo-Miller L.D. Olafsson P. Wang T. Lu B. Nature. 1996; 381: 706-709Crossref PubMed Scopus (956) Google Scholar, T. H. N. J. Neurosci. 1997; PubMed Google Scholar, Pozzo-Miller L.D. A. Lu B. J. Neurosci. 1998; PubMed Google Scholar, M. R.A. J. 1998; PubMed Scopus Google Scholar), and studies showed that BDNF was selectively for of LTP that a presynaptic Patterson S.L. Kandel E.R. A. Neuron. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). activation of post-synaptic TrkB receptors intracellular in induce LTP when with synaptic stimulation E. A. 2002; PubMed Scopus Google Scholar). The of synaptic transmission by BDNF observed in the in E. K. B. J. 1998; PubMed Scopus Google also be at in to the activation of post-synaptic receptors E. T. J. Neurosci. 2002; PubMed Google Scholar, M. K. J. Neurosci. 2002; PubMed Google Scholar). a post-synaptic role of BDNF in synaptic plasticity, and the mechanisms The and of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in with receptor are important in the to and play an important role in the mechanisms of synaptic plasticity Carvalho Duarte C.B. Res. 2003; PubMed Scopus Google Scholar). AMPA receptors are by the of and delivery to the is by the intracellular signaling this we the effect of BDNF on the of AMPA receptors in cultured hippocampal neurons and on Furthermore, we the effect of BDNF on the synaptic delivery of AMPA receptors in CA1 hippocampal for the effects of the neurotrophin in the early phase of LTP. cultures of hippocampal neurons were from the of with and and in and and The were with to and to with and The were in this and were in with The cultures were in a of at for were with BDNF from for the of K252a, actinomycin were 30 min of endogenous extracellular BDNF was with TrkB-IgG for slices were from days and and cultured on M. D. R.A. Neurosci. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). of neurons were with and with with and a of The were with and at a with and the of inhibitors. at for protein in the was the acid and the were with a and from hippocampal slices were in and and were at for and the protein in the was the acid and with at for The of were by and for from cultured hippocampal neurons was with to the of the The of a with was for of was with and in in a of The was at for followed by min at for to the and The was min at and the was to for min and at analysis of gene expression was the The were R.J. J. Neuron. 1996; 16: Full Text Full Text PDF PubMed Scopus Google in The used for of AMPA receptor subunits and for and for and for and for The used for the of endogenous gene were in the of a was to the at a of with in to the and of was with activation of the by min at followed by of a at a at and a at used were at for at the of the phase of were to a analysis to the of the to the of and were mRNA mRNA levels of the gene were used a in The changes in the mRNA levels of receptor subunits in cultured hippocampal neurons were the Accordingly, for neurons and neurons with BDNF for 30 min the by the for were by the for the gene from the same and changes in gene the were by the of the for the gene The to the of at the and the used were at a to the Biotinylation and cultures were not with BDNF and with in and for 30 min Cunha P. M. Carvalho Duarte C.B. J. PubMed Scopus Google Scholar). The was by the with were and were with for at were by at for and the were with were with at for min and D) at for min were for were by in to and were with at and to at was by on the and by The were Ser-831 and and receptor were used days in the organotypic cultures of hippocampal slices, M. D. R.A. Neurosci. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), were with the GluR1 GluR1 the to were from and CA1 and The was with dl-2-amino-5-phosphonovaleric acid and with were with the and were with a were with with of to The were and from the AMPA were at and with in CA1 and was used an of were with the effect of was the was to the 30 min to with with BDNF was from 30 min to the effect of NMDA receptor on AMPA delivery to the was NMDA were blocked analysis was followed by the the in the of BDNF on the of AMPA whether stimulation with BDNF the of receptor cultured hippocampal neurons were with BDNF, for of min to The AMPA receptor GluR2, and protein levels were by BDNF protein in a with effects observed min of stimulation with the neurotrophin and BDNF not protein levels The in GluR1, GluR2, and GluR3 and the effects were observed with BDNF for and 30 of BDNF stimulation the of subunits decreased to to the was GluR3 with the the effect of BDNF on this was not with the results hippocampal BDNF not GluR1 and GluR2 protein levels in neurons cultured for DIV, for with the neurotrophin of and when the endogenous extracellular BDNF was with the protein TrkB-IgG for the levels of GluR1 decreased changes were observed for the GluR2 results indicate that endogenous BDNF the GluR1 protein levels in cultures of hippocampal neurons. of Trk neurotrophin receptors was for of GluR1 and GluR2 AMPA receptor subunits by BDNF in effect of the neurotrophin was observed when the were in the of an of this of receptors of Trk the of GluR1 and GluR2 protein were with BDNF for in the in the of the was it was 30 min stimulation with GluR1 and GluR2 protein levels were by protein levels of AMPA receptor subunits were to was used The results are the of independent in independent analysis was by ANOVA, followed by the whether the effect of BDNF was to an increase in protein we used translation and neurons were with BDNF for in the in the of the translation inhibitors. and abrogated the effect of BDNF on GluR1 and GluR2 subunits of the protein the GluR1 GluR2 protein levels conditions, in with the long of AMPA receptor subunits R.J. S. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, K. E. Neuropharmacology. 1998; 37: PubMed Scopus Google Scholar, R.J. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Taken together, indicate that the effect of BDNF on AMPA receptor subunits is mediated by activation of TrkB receptor and is to an of protein of a in protein BDNF AMPA by transcription of E. T. J. Neurosci. 2002; PubMed Google protein by translation N. M. K. K. Nawa H. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). to for the role of transcription in the of receptor subunits by BDNF we used transcription and actinomycin transcription blocked the effect of BDNF on GluR1 and GluR2 protein but were effect on the of the receptor subunits in the of the neurotrophin with the green showed that BDNF stimulation for 30 min increased the mRNA levels for GluR1, and when the were with the neurotrophin a increase in the mRNA for GluR1 and GluR2 was also observed Taken together, the results indicate that BDNF GluR1 and GluR2 AMPA receptor subunits at the transcription with the results for GluR1 and GluR2, effect of BDNF was observed on the mRNA levels for GluR3 and the mRNA levels of the GluR1 and GluR2 AMPA receptor subunits. The of GluR1 and GluR2 mRNA levels was by of to in to of The were in the of BDNF, 30 min The results are with the and to the gene and are the of independent in independent analysis was by ANOVA, followed by the of BDNF on GluR1 and GluR2 at the a of receptors in neurons is intracellular R.A. 1997; PubMed Scopus Google not in the to the we whether BDNF can the of AMPA receptor subunits to the plasma the effect of BDNF on the of the AMPA receptor subunits GluR1 and GluR2, cultured hippocampal neurons were with BDNF and on the were with and to GluR1 protein associated with the plasma was increased by BDNF 30 min when with with BDNF for was effect The increase observed by BDNF 30 min was blocked by that the in the amount of plasma GluR1 protein BDNF not the GluR2 protein levels at the plasma results indicate that BDNF has a effect on the of AMPA receptor subunits in developing cultured hippocampal neurons. the for the increase in and GluR1 expression that the effects of BDNF on GluR1 and receptor be mediated by signaling with the results in developing BDNF not the expression of GluR1 in cultured hippocampal neurons The delivery of GluR1 subunits to the is by phosphorylation in the GluR1 is on Ser-831 LTP, this phosphorylation is not to induce synaptic delivery of AMPA receptors Carvalho Duarte C.B. Res. 2003; PubMed Scopus Google Scholar, R.J. J. Neuron. 1996; 16: Full Text Full Text PDF PubMed Scopus Google Scholar, A. J.C. R. 2000; PubMed Scopus Google Scholar, M. K. Nature. 2000; PubMed Scopus Google Scholar). of cultured hippocampal neurons with BDNF increased the phosphorylation of GluR1 on by a the amount of GluR1 in the was also increased stimulation with the the of protein that was was not also signaling pathways be involved in GluR1 phosphorylation Trk receptor and Ser-831 is a phosphorylation site for protein kinase C and Ca2+-calmodulin-dependent protein kinase Carvalho Duarte C.B. Res. 2003; PubMed Scopus Google Scholar, R.J. J. Neuron. 1996; 16: Full Text Full Text PDF PubMed Scopus Google Scholar), the effect of the kinase and was of and with and GluR1 phosphorylation on that pathways to the effect of BDNF of BDNF on of AMPA the role of BDNF in the of AMPA receptors the in CA1 neurons of hippocampal organotypic slices of with a expression system, to the of homomeric AMPA receptors the GluR1 A. J.C. R. 2000; PubMed Scopus Google Scholar). receptors are J. M. A. M. E. C. S. PubMed Scopus Google Scholar, M. M. S. PubMed Scopus Google Scholar, T.A. N. H. B. PubMed Scopus Google Scholar), and to the the at with effect on the synaptic delivery of AMPA receptors to the can be an increase in the the at the at A. J.C. R. 2000; PubMed Scopus Google Scholar). of GluR1 in CA1 hippocampal neurons not increase the of synaptic and and in that GluR1 is not synapses A. J.C. R. 2000; PubMed Scopus Google Scholar). the of homomeric neurons was increased with BDNF for 30 min to and and in BDNF effect on the of and The effect of BDNF was to that observed in GluR1 was with a of and and in is to induce synaptic delivery of AMPA receptors A. J.C. R. 2000; PubMed Scopus Google Scholar, J.C. R. J. Neurosci. 2002; PubMed Google Scholar). of the Trk receptors with synaptic delivery of AMPA receptors induced by BDNF and Taken together, the results indicate that BDNF induces a delivery of GluR1 homomeric receptors and that this effect is mediated by of BDNF to Trk stimulation was shown to induce a delivery of AMPA receptors and receptor in by a mechanism activation of NMDA receptors Hayashi R.J. K. R. 1999; PubMed Scopus Google Scholar). whether synaptic delivery of AMPA receptors induced by BDNF activation of NMDA were in the of the NMDA receptor of the slices with for 30 min not the increase in the induced by BDNF and of hippocampal slices with BDNF for increased GluR1 phosphorylation on Ser-831 and in with the results in cultures of hippocampal neurons in GluR1 phosphorylation was for The activation of Trk receptors by BDNF was by an that in a in the Trk of hippocampal slices with BDNF for 30 min increased Trk showed that the GluR1 and Trk protein levels not in the slices the used The effect of BDNF on GluR1 phosphorylation was phosphorylation of GluR2 on the phosphorylation site Carvalho Duarte C.B. Res. 2003; PubMed Scopus Google was observed is that BDNF plays an important role in synaptic plasticity (1Poo M.M. Nat. Rev. Neurosci. 2001; 2: 24-32Crossref PubMed Scopus (1532) Google Scholar, B. 2003; 10: PubMed Scopus Google Scholar, J. S. R.A. A. Black I.B. J. Neurosci. PubMed Scopus Google Scholar), particularly in LTP induced by high frequency stimulation G. R. Bonhoeffer T. A. J. Neurosci. 1999; 19: PubMed Google Scholar, E.M. Curr. Opin. Neurobiol. 1999; PubMed Scopus Google Scholar, P. Neurosci. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), in late phase transcription activation and protein Kandel E.R. J. Neurosci. 1996; 16: PubMed Google Scholar). Accordingly, LTP is impaired in the hippocampal region of and knock-out mice (3Korte M. Carroll P. Wolf E. Brem G. Thoenen H. Bonhoeffer T. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8856-8860Crossref PubMed Scopus (1209) Google Scholar, 4Patterson S.L. Abel T. Deuel T.A.S. Martin K.C. Rose J.C. Kandel E.R. Neuron. 1996; 16: 1137-1145Abstract Full Text Full Text PDF PubMed Scopus (1038) Google Scholar, M. D. R. K. V. C. Bonhoeffer T. R. Neuron. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B. A. E. K. Wang D. R.A. Lu B. Reichardt L.F. J. Neurosci. 2000; PubMed Google Scholar). the a was also shown M. D. R. K. V. C. Bonhoeffer T. R. Neuron. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the mechanisms BDNF to LTP are not fully understood. this we show that Trk receptor activation by BDNF up-regulates GluR1 and GluR2 protein levels in cultured hippocampal by transcription BDNF also GluR3 protein effect on the mRNA for this receptor was The neurotrophin also induced phosphorylation of GluR1 on by and CaMKII, and promoted synaptic delivery of AMPA receptors in the CA1 region of the with BDNF GluR1 and GluR2 protein levels to the same in cultured hippocampal neurons and but selectively increased the amount of GluR1 subunits associated with the plasma indicate that the delivery of GluR1 and GluR2 subunits to the is shown for synaptic delivery of the AMPA receptor subunits in the S. Hayashi R. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. V. M. Nat. Neurosci. 2001; PubMed Scopus Google Scholar). Furthermore, we that the BDNF acutely GluR1 associated with the plasma by the translation be to the delivery of receptors to the plasma and/or to an increased of the plasma receptors by with Trk receptor stimulation. The effects of BDNF on the plasma GluR1 protein levels signaling by Trk stimulation with BDNF, when Trk receptors are to M.M. Carvalho Carvalho A.P. Duarte C.B. PubMed Scopus Google Scholar), the receptor subunits in the were to the with the results in when is particularly P. P. G. J. Neurosci. PubMed Google Scholar), of BDNF effect on GluR1 and GluR2 protein levels in hippocampal neurons cultured for and of endogenous extracellular BDNF with the protein TrkB-IgG selectively decreased the GluR1 that BDNF has a effect on GluR1 protein levels results that the of effect of BDNF on GluR1 protein levels in hippocampal cultures and on the amount of receptors be to the of endogenous BDNF, to the of GluR1, an effect of of the also the results effect of BDNF on GluR1 protein levels in the organotypic slices studies also shown that BDNF induces synaptic delivery of AMPA receptors in CA1 neurons of hippocampal organotypic slices by a mechanism independent of NMDA receptor with the role of NMDA receptors in synaptic delivery of AMPA receptors tetanic stimulation Hayashi R.J. K. R. 1999; PubMed Scopus Google Scholar). The synaptic delivery of GluR1 induced by BDNF was to the Trk and was associated with the phosphorylation of the protein in the and phosphorylation site Carvalho Duarte C.B. Res. 2003; PubMed Scopus Google Scholar). GluR1 phosphorylation in Ser-831 was also observed induction of LTP in synapses M. K. Nature. 2000; PubMed Scopus Google Scholar). BDNF not GluR1 phosphorylation in is high frequency stimulation of synapses M. K. Nature. 2000; PubMed Scopus Google Scholar). GluR1 phosphorylation in Ser-831 is not to induce synaptic delivery of AMPA receptors A. J.C. R. 2000; PubMed Scopus Google Scholar), the effect of BDNF also GluR1 phosphorylation on of this site is increased hippocampal LTP, an important role in synaptic of GluR1 J. Kang J. R. Neuron. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). BDNF induce the phosphorylation of a to the of a and the of GluR1 subunits the synapse. of GluR1 on Ser-831 also the with a protein that the receptor at the plasma The effect of BDNF on synaptic delivery of GluR1 was to that observed in a of was that signaling mechanisms be of cultured hippocampal neurons also increased the phosphorylation of GluR1 on and this effect was by of and CaMKII, that pathways are involved in the GluR1 phosphorylation and on the delivery of AMPA receptors to the synapse. with the role of and in GluR1 activation of TrkB receptors the phospholipase Cγ to PKC, and from intracellular D.R. Miller F.D. Curr. Opin. Neurobiol. 2000; 10: 381-391Crossref PubMed Scopus (1670) Google Scholar, 11Huang E.J. Reichardt L.F. Annu. Rev. Biochem. 2003; 72: 609-642Crossref PubMed Scopus (1982) Google Scholar). this signaling is involved in the synaptic changes from of BDNF to the of synaptic at the of by AMPA receptors at the M.M. Nature. PubMed Scopus Google Scholar). Furthermore, of phospholipase Cγ by TrkB receptors was shown to play a role in hippocampal LTP Bonhoeffer T. R. M. Neuron. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). activation of NMDA receptors induces a delivery of AMPA receptors to the and in Hayashi R.J. K. R. 1999; PubMed Scopus Google Scholar), this not for the effect of BDNF, we effect of the NMDA receptor on delivery of GluR1 subunits to the synapse. of NMDA receptors was also shown not to LTP at to synapses in the in with the high frequency LTP, on the activation of NMDA receptors E. T. J. Neurosci. 2002; PubMed Google Scholar). to the effects on delivery of GluR1 subunits to the in hippocampal CA1 and to the plasma in developing cultured hippocampal BDNF also GluR1, GluR2, and GluR3 protein levels in the effect was to the of the Trk followed by a in intracellular signaling M.M. Carvalho Carvalho A.P. Duarte C.B. PubMed Scopus Google Scholar, R. E. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The in AMPA receptor subunits induced by BDNF was to an increase in transcription by the effect of transcription followed by of the receptor subunits. The role of transcription on the effect of BDNF on the protein levels of the GluR1 and GluR2 subunits is not BDNF is to transcription of P. Neurosci. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Neurosci. 2003; PubMed Google and to modulate transcription the late phase LTP E. T. J. Neurosci. 2002; PubMed Google Scholar). with the of cultured neurons with BDNF also increased GluR1 and protein but effect on the mRNA for the receptor subunits was M. J. K. Yamaguchi T. Nawa H. 1999; PubMed Scopus Google Scholar, T. K. M. H. N. Nawa H. Neurosci. 2003; PubMed Scopus Google Scholar). in this the stimulation of neurotrophin receptors from early in development changes in The signaling mechanisms involved in the increase in the transcription of GluR1 and GluR2 in hippocampal neurons to BDNF to be studies shown GluR1 protein levels be by the and kinase of the of N. G. T. G. M. M. N. R.A. Wang J. D. J. PubMed Scopus Google Scholar), and by the kinase also (9Narisawa-Saito M. Silva A.J. Yamaguchi T. Hayashi T. Yamamoto T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2461-2466Crossref PubMed Scopus (60) Google Scholar). in a showed that the expression of GluR2 can be by BDNF, through a mechanism a the GluR2 S. C. H. M. E.J. J. Neurosci. 2000; PubMed Scopus Google Scholar). results are in with results and with the effects observed in neurons to BDNF, in the mRNA for GluR2 was observed M. J. K. Yamaguchi T. Nawa H. 1999; PubMed Scopus Google Scholar). to the effect of BDNF on the mRNA levels for GluR1 and GluR2, for the in the AMPA receptor subunits in cultured hippocampal a showed that BDNF also increased GluR1 protein levels in J. Neurosci. PubMed Scopus Google Scholar). mediated by a of to increase the amount GluR1 high frequency stimulation. of receptors to the to LTP. stimulation of cultures with BDNF also increased the of the AMPA and H. M. K. H. M. Hayashi N. Nawa H. 2003; PubMed Scopus Google Scholar). Under the same was an increase in the GluR1 and GluR2 and was to play a role in the of AMPA receptors by BDNF H. M. K. H. M. Hayashi N. Nawa H. 2003; PubMed Scopus Google Scholar). to be whether BDNF induces a and increase in the protein levels of AMPA to the receptors at the synapse. results that BDNF plays a direct role in the early phase of synaptic plasticity by the delivery of GluR1 subunits to the synapse. Furthermore, BDNF AMPA receptor subunits in developing hippocampal neurons and induced an increase in the of receptors associated with the a of of of for the of the and for the of