Brain-derived Neurotrophic Factor Regulates Surface Expression of α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic Acid Receptors by Enhancing the N-Ethylmaleimide-sensitive Factor/GluR2 Interaction in Developing Neocortical Neurons

Abstract

In hippocampal neurons, the exocytotic process of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors is known to depend on activation ofN-methyl-d-aspartate channels and its resultant Ca2+ influx from extracellular spaces. Here we found that brain-derived neurotrophic factor (BDNF) induced a rapid surface translocation of AMPA receptors in an activity-independent manner in developing neocortical neurons. The receptor translocation became evident within hours as monitored by [3H]AMPA binding and was resistant against ionotropic glutamate receptor antagonists as evidenced with surface biotinylation assay. This process required intracellular Ca2+ and was inhibited by the blockers of conventional exocytosis, brefeldin A, botulinum toxin B, andN-ethylmaleimide. To explore the translocation mechanism of individual AMPA receptor subunits, we utilized the human embryonic kidney (HEK) 293 cells carrying the BDNF receptor TrkB. After the single transfection of GluR2 cDNA or GluR1 cDNA into HEK/TrkB cells, BDNF triggered the translocation of GluR2 but not that of GluR1. Subsequent mutation analysis of GluR2 carboxyl-terminal region indicated that the translocation of GluR2 subunit in HEK293 cells involved its N-ethylmaleimide-sensitive factor-binding domain but not its PDZ-interacting site. Following co-transfection of GluR1 and GluR2 cDNAs, solid phase cell sorting revealed that GluR1 subunits were also able to translocate to the cell surface in response to BDNF. An immunoprecipitation assay confirmed that BDNF stimulation can enhance the interaction of GluR2 withN-ethylmaleimide-sensitive factor. These results reveal a novel role of BDNF in regulating the surface expression of AMPA receptors through a GluR2-NSF interaction. In hippocampal neurons, the exocytotic process of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors is known to depend on activation ofN-methyl-d-aspartate channels and its resultant Ca2+ influx from extracellular spaces. Here we found that brain-derived neurotrophic factor (BDNF) induced a rapid surface translocation of AMPA receptors in an activity-independent manner in developing neocortical neurons. The receptor translocation became evident within hours as monitored by [3H]AMPA binding and was resistant against ionotropic glutamate receptor antagonists as evidenced with surface biotinylation assay. This process required intracellular Ca2+ and was inhibited by the blockers of conventional exocytosis, brefeldin A, botulinum toxin B, andN-ethylmaleimide. To explore the translocation mechanism of individual AMPA receptor subunits, we utilized the human embryonic kidney (HEK) 293 cells carrying the BDNF receptor TrkB. After the single transfection of GluR2 cDNA or GluR1 cDNA into HEK/TrkB cells, BDNF triggered the translocation of GluR2 but not that of GluR1. Subsequent mutation analysis of GluR2 carboxyl-terminal region indicated that the translocation of GluR2 subunit in HEK293 cells involved its N-ethylmaleimide-sensitive factor-binding domain but not its PDZ-interacting site. Following co-transfection of GluR1 and GluR2 cDNAs, solid phase cell sorting revealed that GluR1 subunits were also able to translocate to the cell surface in response to BDNF. An immunoprecipitation assay confirmed that BDNF stimulation can enhance the interaction of GluR2 withN-ethylmaleimide-sensitive factor. These results reveal a novel role of BDNF in regulating the surface expression of AMPA receptors through a GluR2-NSF interaction. The neurotrophins, nerve growth factor, brain-derived neurotrophic factor (BDNF), 1The abbreviations used are: BDNF, brain-derived neurotrophic factor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; NMDA, N-methyl-d-aspartate; NEM, N-ethylmaleimide; αCAMKII, α Ca2+/calmodulin-dependent kinase II; NSF, N-ethylmaleimide-sensitive factor; HEK, human embryonic kidney; PKC, protein kinase C; aa, amino acid(s); FITC, fluorescein isothiocyanate; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; ATPγS, adenosine 5′-O-(thiotriphosphate). neurotrophin-3, and neurotrophin-4/5, are implicated as important regulators of synaptic development and plasticity in both central and peripheral nervous systems. In particular, activity-dependent synthesis and release of neurotrophins are suggested to be key modulators of neuronal development and synaptic plasticity. BDNF can exert strong neurotrophic activities on immature brain neurons with a subchronic time scale of days. BDNF enhances the dendritic growth, induces synaptogenesis (1McAllister A.K. Katz L.C. Lo D.C. Neuron. 1997; 18: 767-778Google Scholar, 2Lom B. Cohen-Cory S. J. Neurosci. 1999; 19: 9928-9938Google Scholar), and induces various neurochemical phenotypes of developing excitatory and inhibitory neurons (3Xiong H. Yamada K. Han D. Nabeshima T. Enikolopov G. Carnahan J. Nawa H. Eur. J. Neurosci. 1999; 11: 1567-1576Google Scholar, 4Narisawa-Saito M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar, 5Mizuno K. Carnahan J. Nawa H. Dev. Biol. 1994; 165: 243-256Google Scholar, 6Sato M. Suzuki K. Nakanishi S. J. Neurosci. 2001; 21: 3797-3805Google Scholar). The biological activity of neurotrophins on the induction of postsynaptic components and/or development of postsynaptic neurons needs to be evaluated, and their underlying molecular mechanisms remain to be characterized in various types of neurons. In addition to such chronic activity of BDNF for days, application of BDNF to cultured neurons enhances excitatory glutamatergic synaptic transmission with increased efficacy of glutamate release from the presynaptic neuron (7Takei N. Numakawa T. Kozaki S. Sakai N. Endo Y. Takahashi M. Hatanaka H. J. Biol. Chem. 1998; 273: 27620-27624Google Scholar, 8Schinder A.F. Berninger B. Poo M. Neuron. 2000; 25: 151-163Google Scholar, 9Jovanovic J.N. Czernik A.J. Fienberg A.A. Greengard P. Sihra T.S. Nat. Neurosci. 2000; 3: 323-329Google Scholar, 10Xu B. Gottschalk W. Chow A. Wilson R.I. Schnell E. Zang K. Wang D. Nicoll R.A., Lu, B. Reichardt L.F. J. Neurosci. 2000; 20: 6888-6897Google Scholar). Neurotrophins also acutely enhance postsynaptic responsiveness ofN-methyl-d-aspartate (NMDA)-type glutamate receptors in mature synapses (11Suen P.C., Wu, K. Levine E.S. Mount H.T., Xu, J.L. Lin S.Y. Black I.B. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8191-8195Google Scholar). In addition, endogenous neuronal BDNF is required for various forms of synaptic plasticity (12Kang H. Schuman E.M. Science. 1995; 267: 1658-1662Google Scholar, 13Patterson S.L. Abel T. Deuel T.A. Martin K.C. Rose J.C. Kandel E.R. Neuron. 1996; 16: 1137-1145Google Scholar, 14Figurov A. Pozzo-Miller L.D. Olafsson P. Wang T. Lu B. Nature. 1996; 381: 706-709Google Scholar). However, the latest studies demonstrate that BDNF is released from nerve terminals in an activity-dependent manner and act on target neurons or postsynaptic sites (15Griesbeck O. Canossa M. Campana G. Gartner A. Hoener M.C. Nawa H. Kolbeck R. Thoenen H. Microsc. Res. Tech. 1999; 45: 262-275Google Scholar, 16Kohara K. Kitamura A. Morishima M. Tsumoto T. Science. 2001; 291: 2419-2423Google Scholar). Accordingly, anterograde neurotrophic functions of BDNF have now been established (17Nawa H. Takei N. Trends Neurosci. 2001; 24: 683-684Google Scholar). A large variety of molecules interacting with α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor subunits have been identified and characterized; SAP97 associates with the COOH termini of GluR1 subunits, whereas GRIP/ABP and Pick1 bind to those of GluR2 and GluR3 subunits (18Dong H. O'Brien R.J. Fung E.T. Lanahan A.A. Worley P.F. Huganir R.L. Nature. 1997; 386: 279-284Google Scholar, 19Srivastava S. Osten P. Vilim F.S. Khatri L. Inman G. States B. Daly C. DeSouza S. Abagyan R. Valtschanoff J.G. Weinberg R.J. Ziff E.B. Neuron. 1998; 21: 581-591Google Scholar, 20Dev K.K. Nishimune A. Nakanishi S. 1999; Scholar, J. J. Huganir R.L. Neuron. 1999; Scholar). The intracellular domain of GluR1 protein associates with various as such as and that of GluR2 with factor T. H. M. T. Nature. 1999; Scholar, Y. P. Nature. 1997; Scholar, A. E. J. M. Nakanishi S. Neuron. 1998; 21: Scholar, P. S. Inman Vilim F.S. Khatri L. States S. T.A. Ziff E.B. Neuron. 1998; 21: Scholar). The interacting carrying are suggested to to the and of AMPA receptors the postsynaptic of the hippocampal neurons S. Osten P. Vilim F.S. Khatri L. Inman G. States B. Daly C. DeSouza S. Abagyan R. Valtschanoff J.G. Weinberg R.J. Ziff E.B. Neuron. 1998; 21: 581-591Google Scholar, R.J. L.F. Huganir R.L. 1998; Scholar, Y. A. J.C. R. Science. 2000; Scholar, M. Nat. Neurosci. 2001; Scholar). the interaction is also suggested to have in the of AMPA receptors in such excitatory neurons. to synaptic plasticity as evidenced by of the interaction GluR2 and with a hippocampal J. L. J. E. Neuron. 1999; Scholar, A. R. T.A. Neuron. 1999; 24: Scholar). In to the AMPA receptors in hippocampal neurons, the of the AMPA receptor in types of neurons are that chronic BDNF and protein of AMPA receptor subunits in neocortical their expression M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar, M. A.J. Yamaguchi T. T. T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). with is synaptic AMPA receptor expression in BDNF M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar). This process on a mechanism and chronic stimulation of BDNF for days. In the we found that BDNF of AMPA receptors in cultured neocortical neurons. cultured neurons as as the of human embryonic kidney (HEK) cells, we the molecular mechanism underlying the rapid BDNF on surface translocation of AMPA receptor characterized to the process and the plasticity The of the individual subunit to the of the receptor is also and of embryonic or were and a neurons were in or in as M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar, M. A.J. Yamaguchi T. T. T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; N. K. K. Takahashi M. Endo Y. Hatanaka H. J. 1997; Scholar). human BDNF was HEK293 cells were with a carrying the cDNA in by S. with Ca2+ were in and the were and cells were with cDNA for or its the and their expression and were and to the BDNF were with the known to or brefeldin A botulinum toxin (7Takei N. Numakawa T. Kozaki S. Sakai N. Endo Y. Takahashi M. Hatanaka H. J. Biol. Chem. 1998; 273: 27620-27624Google Scholar), and A were with various kinase and or with and or cells were with BDNF for to and with in and on Huganir R.L. O'Brien R.J. J. Neurosci. 1997; Scholar). was with were with and for were in After for protein in was in the of and protein were by with was to a by were with and with the was with to by with The were COOH against GluR2 intracellular domain to a acid to the COOH of M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar), to of M. and The of the was by neurons or cells were with and [3H]AMPA was to with the and with to AMPA were with AMPA on for as Y. T. M. H. K. Takei N. Nawa H. J. Biol. Chem. 2001; Scholar). An of AMPA was to to [3H]AMPA binding to After rapid with cells were with and the of cell was a sorting was a HEK293 cells in were with K. Y. Nawa H. J. 1999; by the After cells were with an and the against the intracellular domain M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar). for GluR1 and GluR2 was with the and the An was used to and and a was used for The amino and amino of GluR2 were the as a The of the binding region was with a to the from the was confirmed by and the expression of the GluR2 was by cells were in immunoprecipitation and were for and the was used for S. J. H. D. Huganir R.L. Neuron. 1998; 21: Scholar). from were in immunoprecipitation M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar), and was on a The was with BDNF for and for and the was in immunoprecipitation the were with of protein and were with for The was with protein and with immunoprecipitation in and to by with analysis was analysis of by the was to with and factor. from cell the was were with or and as To BDNF stimulation can AMPA receptor on the cell surface or [3H]AMPA binding assay was with cultured neocortical neurons for and with or BDNF After a with BDNF, various of [3H]AMPA were to and the binding of the to neurons was The of [3H]AMPA were to the and the and the of the AMPA receptors were on the cell surface of the AMPA receptors on the cell surface increased from to The of the AMPA receptors increased from to The time of the binding activity of the AMPA receptors was by neurons with BDNF for various of time and by to a of [3H]AMPA The AMPA binding to neocortical became evident a with BDNF and increased of of These results reveal that BDNF rapid of AMPA to the AMPA receptor on the cell To the mechanism of rapid of AMPA known to for A, botulinum toxin B, and or were to of neocortical neurons to BDNF (7Takei N. Numakawa T. Kozaki S. Sakai N. Endo Y. Takahashi M. Hatanaka H. J. Biol. Chem. 1998; 273: 27620-27624Google After BDNF the of AMPA receptors on the cell surface was by assay with A, to increased of surface AMPA receptors and BDNF their In the brefeldin A, botulinum toxin B, and NEM, inhibited or the BDNF The that the in AMPA receptors an exocytotic process of the of Ca2+ and kinase on cell surface translocation of AMPA brefeldin botulinum a with BDNF, [3H]AMPA binding assay was in cultured neurons with a of the binding of [3H]AMPA was in with addition of of AMPA and from of [3H]AMPA [3H]AMPA binding was with protein were not by was and in of blockers and were in with in a After a with BDNF, [3H]AMPA binding assay was in cultured neurons with a of the binding of [3H]AMPA was in with addition of of AMPA and from of [3H]AMPA [3H]AMPA binding was with protein were not by was and in of blockers and were in with we the of Ca2+ its BAPTA, and its Ca2+ was with whereas extracellular Ca2+ was with cultured neocortical neurons were with BDNF for inhibited the in [3H]AMPA In The that the surface translocation of AMPA receptors by BDNF the exocytotic triggered by intracellular Ca2+ M. D. J. Scholar). BDNF is known to intracellular of and protein In addition, protein kinase and are implicated in the of AMPA receptors R.J. L.F. Huganir R.L. 1998; Scholar, Y. A. J.C. R. Science. 2000; Scholar, M. Nat. Neurosci. 2001; Scholar). To explore intracellular to the surface AMPA receptor cultured neurons were with BDNF in the of kinase protein and the in [3H]AMPA and the [3H]AMPA BDNF the [3H]AMPA binding in the of This that kinase the translocation of AMPA the of [3H]AMPA binding was by and as as by the kinase be an that the surface AMPA receptor To the BDNF on of individual AMPA receptor subunit cultured neocortical neurons were with or BDNF. Following the on cell were with and to The GluR1 and were increased by BDNF with cells In AMPA receptor protein were also increased in BDNF is known to glutamate release from cultured neurons N. K. K. Takahashi M. Endo Y. Hatanaka H. J. 1997; Scholar). the activation of glutamate receptors involved in the surface of AMPA To the of endogenous glutamate to the BDNF both and glutamate receptors were by their and in In the of BDNF increased the surface expression of the AMPA receptor These results that BDNF the of the AMPA receptors on neuronal of excitatory synaptic To explore the molecular mechanism for the surface translocation of AMPA we to AMPA receptor translocation in This the of presynaptic or activity-dependent HEK293 cells carrying receptors were established with of human the cDNA for AMPA receptor subunit into the cells, the of BDNF on the surface expression of receptor GluR1 or were by the cell surface biotinylation assay. BDNF triggered an in surface protein of GluR2 as a with BDNF The of surface expression was for GluR2 of In surface expression of GluR1 as as that of was not and of This the that BDNF of intracellular The cell surface of the AMPA receptor subunits was by the assay [3H]AMPA cells were with BDNF, [3H]AMPA binding activity on the cell surface was increased in the cells carrying GluR2 but not GluR1. These results that the of BDNF on translocation the GluR2 subunit in have found that BDNF can enhance to protein synthesis in neurons N. M. K. K. Nawa H. J. Biol. Chem. 2001; Scholar). we of protein synthesis to the surface AMPA receptor both in neurons and HEK293 The protein in GluR1 and the rapid surface in AMPA a with BDNF to GluR1 and in protein from whereas the increased surface [3H]AMPA binding in and surface AMPA receptor biotinylation on cells and also the of and The of protein synthesis and in a in AMPA binding activity for and for the of protein to the of a surface receptor in the of the BDNF stimulation the of the in AMPA binding activity as in BDNF surface AMPA binding to neurons was increased a with BDNF and the In addition, the AMPA binding activity of the and was that of In cultured cells, also to the AMPA receptor translocation induced by BDNF. The surface biotinylation assay transfection of GluR2 cDNA revealed that surface AMPA receptor were increased by a with BDNF, in the of the for and for BDNF, the surface receptor was in the of protein with These results that the AMPA receptor translocation is from the N. M. K. K. Nawa H. J. Biol. Chem. 2001; Scholar). To the mechanism of rapid of AMPA receptors in HEK293 cells with that in neurons, the that A and or were to to BDNF application After a with BDNF, cell GluR2 protein was on cells by surface and the of the GluR2 protein and inhibited the cell surface as A to the BDNF The target protein of the is known as factor is implicated in Nature. Scholar). that BDNF the surface translocation of GluR2 subunits in the cells through exocytotic have been identified in GluR2 domain that with G. 2000; the amino of the binding region (18Dong H. O'Brien R.J. Fung E.T. Lanahan A.A. Worley P.F. Huganir R.L. Nature. 1997; 386: 279-284Google Scholar, 19Srivastava S. Osten P. Vilim F.S. Khatri L. Inman G. States B. Daly C. DeSouza S. Abagyan R. Valtschanoff J.G. Weinberg R.J. Ziff E.B. Neuron. 1998; 21: 581-591Google Scholar, 20Dev K.K. Nishimune A. Nakanishi S. 1999; Scholar, J. J. Huganir R.L. Neuron. 1999; and an binding A. E. J. M. Nakanishi S. Neuron. 1998; 21: Scholar, P. S. Inman Vilim F.S. Khatri L. States S. T.A. Ziff E.B. Neuron. 1998; 21: Scholar, S. J. H. D. Huganir R.L. Neuron. 1998; 21: Scholar). The interacting with GluR2 subunits and Pick1 R. K.K. Neuron. 2000; Scholar, A. Khatri L. M. M. Ziff E.B. Weinberg R.J. J. Neurosci. 2001; 21: Scholar). These interacting are implicated to in regulating the and of AMPA receptors the postsynaptic To BDNF on the GluR2 COOH interacting we GluR2 a binding domain and and an binding domain to their analysis for GluR2 was used to that was GluR2 expression of in the cells After BDNF the cell surface of GluR2 protein was by the biotinylation assay. BDNF the surface expression of and in GluR2 of of and of but not in of the that is involved in surface of the AMPA receptor The interaction of GluR2 with is to be P. S. Inman Vilim F.S. Khatri L. States S. T.A. Ziff E.B. Neuron. 1998; 21: Scholar). To that BDNF enhances the interaction GluR2 and in the immunoprecipitation with an GluR2 was in cell from cells or from the neocortical of GluR2 and BDNF was in from both results that BDNF AMPA receptor by the interaction. are a variety of of AMPA receptor subunits that can the J.C. Trends Neurosci. 1994; Scholar). Accordingly, the as to the of AMPA receptor subunits, such as in response to BDNF. the transfection into cells with an of a cell The of into The of GluR1 was monitored by its in cells as as cell cell In GluR2 for cells was The was to the of cells that GluR1 cell In the single transfection of GluR1 cell surface for subunit was a of BDNF A and the transfection was with that of GluR2 the surface for GluR1 was not with that of the GluR1 single transfection and the was with BDNF, GluR1 on cell surface was and for GluR2 was increased by BDNF not In cDNA for the GluR2 was with that for the GluR2 the binding the GluR1 was BDNF stimulation to the surface GluR1 to the for the of GluR2 we on the strong cells, the BDNF was in the that the BDNF also protein of the or its subunit to the receptor an of the interaction on the receptor to be results that BDNF the of the AMPA receptor In the we found that BDNF is a of AMPA receptor in developing neocortical neurons. The binding the cell surface and the cell sorting assay that AMPA receptor carrying GluR2 subunits can be from the to the cell surface in response to BDNF The of AMPA receptor on a rapid time scale of to hours and the in the AMPA receptor The exocytotic process for AMPA receptors to depend on the interaction of GluR2 subunits with and on intracellular Ca2+ The for as as for to This with the that a central role in the AMPA receptor for hippocampal Y. A. J.C. R. Science. 2000; Scholar, D. R. Nature. 1995; Scholar, Nicoll Neuron. 1995; Scholar, S. Y. R. 2001; Scholar). the process a for plasticity or development of AMPA postsynaptic of neocortical neurons. cells, we the molecular of AMPA subunit and its to the translocation of the receptor In response to BDNF, GluR2 subunits were to the cell GluR1 as as GluR2 the binding to translocate to the cell the results from the cells with those from neocortical neurons, we the that intracellular of AMPA receptor subunits or in neurons D. R. Nature. 1995; Scholar, Nicoll Neuron. 1995; Scholar, S. Y. R. 2001; Scholar). the of the AMPA receptor is in various types of cells of or The the that various neurotrophic BDNF can the of the AMPA receptor on the subunit and interacting molecules S. Y. R. 2001; Scholar). Neurotrophins have been with to their activity on presynaptic components and functions E.M. 1999; Scholar, M. Nat. Neurosci. 2001; Scholar). BDNF induces expression of presynaptic and synthesis of to enhance presynaptic N. K. K. Takahashi M. Endo Y. Hatanaka H. J. 1997; Scholar). and studies of BDNF revealed that BDNF is in presynaptic and released postsynaptic neurons in an activity-dependent manner (15Griesbeck O. Canossa M. Campana G. Gartner A. Hoener M.C. Nawa H. Kolbeck R. Thoenen H. Microsc. Res. Tech. 1999; 45: 262-275Google Scholar, 16Kohara K. Kitamura A. Morishima M. Tsumoto T. Science. 2001; 291: 2419-2423Google Scholar). The for its anterograde activity the biological of the AMPA receptor developing postsynaptic both and sites an protein receptor mechanism Nature. Scholar, C. H. M. Nicoll Neuron. 1999; 24: Scholar). The surface translocation of AMPA receptor subunits various of exocytotic The blockers of exocytosis, brefeldin A, botulinum toxin B, and NEM, the BDNF This process was from the conventional exocytotic as in The for the AMPA receptors a The postsynaptic translocation of AMPA receptors an of Ca2+ from the intracellular whereas presynaptic release of a from extracellular spaces. In BDNF is known to an intracellular Ca2+ R.J. N. D. Reichardt L.F. J. 2000; Scholar). The blockers for kinase the surface translocation of AMPA is with the that receptor protein kinase R. K. H. G. P. J. 1999; Scholar). In particular, the activation of is J. Biol. Chem. 2001; that PKC, is by a A process be in the interaction and the AMPA receptor Subsequent studies the activation of kinase BDNF stimulation is able to enhance the interaction and the AMPA receptor of the AMPA receptor expression in neocortical was by cell and M. A.J. Yamaguchi T. T. T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). or in a of AMPA receptors and the of the receptor translocation not neocortical of various neuronal neurons and neurons. studies that the of neurons to BDNF was neurons in the Y. M. K. S. N. and H. In the of the on the AMPA receptor translocation is in with the that is from neocortical neurons B. Zang K. Reichardt L.F. Neuron. 2000; Scholar). The of the BDNF on neurons the of the surface AMPA expression of neurons, of cells, the in neurons, the endogenous neuronal activity in and surface translocation of AMPA receptors in neurons in a In we found of the and the on of the surface AMPA receptors in or of AMPA receptor channels is implicated in synaptic plasticity of established brain D. R. Nature. 1995; Nicoll Neuron. 1995; Scholar). activation to is with postsynaptic translocation of AMPA receptors from intracellular in glutamatergic neurons, the AMPA receptor GluR1 Y. A. J.C. R. Science. 2000; Scholar, S. Y. R. 2001; Scholar). be a of the receptors from of the postsynaptic M. M. Nat. Neurosci. 2001; Scholar). the studies that the AMPA receptor is to or synaptic in such excitatory neurons J. L. J. E. Neuron. 1999; Scholar, A. R. T.A. Neuron. 1999; 24: C. H. M. Nicoll Neuron. 1999; 24: Scholar). activity and the resultant influx of extracellular Ca2+ are known to the receptor in hippocampal neurons S. Y. R. 2001; Scholar, Neuron. 2000; Scholar). This process is suggested to the COOH of the AMPA receptor and of the postsynaptic carrying In the exocytotic process of GluR2 subunits in hippocampal neurons its interaction with J. L. J. E. Neuron. 1999; Scholar, A. R. T.A. Neuron. 1999; 24: Scholar, C. H. M. Nicoll Neuron. 1999; 24: Scholar). with individual neurons are to molecular mechanisms underlying the of AMPA receptor individual types of brain neurons on and the translocation of individual AMPA receptor subunits is an the neurotrophins, BDNF increased AMPA receptor protein in neocortical M. Carnahan J. Araki K. Yamaguchi T. Nawa H. Neuroscience. 1999; 88: 1009-1014Google Scholar). growth factor and growth factor to have a on the expression of the AMPA subunits, the neuronal be M. A.J. Yamaguchi T. T. T. Nawa H. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). latest studies that chronic application of BDNF for also expression of various to of AMPA receptors H. Neurosci. 2001; Scholar). This process the interaction AMPA receptors and their In the of the interacting of GluR2 the surface translocation and the in the GluR2 such a process the surface translocation of the receptors to their functions neurotrophic neuronal and In those postsynaptic and/or phenotypes have been are important in both central and peripheral synaptic These the synaptic expression of receptor subunit in the and that of receptors in the brain M. M. Lu, A. Nature. 1997; Y. B. J. Neurosci. 2001; 21: Scholar). cell surface translocation of receptors as as that of the AMPA receptor GluR1 Y. P. Nature. 1997; Scholar, M. M. Nat. Neurosci. 2001; Scholar). the large variety of neurotrophic in the be to the of various receptors in neuronal development and such results in the of postsynaptic sites in are to M. J. and H. for and on for the human BDNF, S. and K. for S. for M. Takahashi for an Y. and Y. for the and and K. for