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J. Biol. Chem., Vol. 282, Issue 17, 12619-12628, April 27, 2007

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Brain-derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery of-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons^*

Margarida V. Caldeira¹, Carlos V. Melo, Daniela B. Pereira, Ricardo Carvalho, Susana S. Correia, Donald S. Backos, Ana Luísa Carvalho, José A. Esteban, and Carlos B. Duarte²

From the Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, 3004-517 Coimbra, Portugal and the Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

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 -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 (-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.

Received for publication, January 22, 2007

^* This work was supported by Fundação para a Ciência e a Tecnologia and Fundo Europeu de Desenvolvimento Regional (Grants POCTI/BCI/46466/2002 and SFRH/BD/9692/2002). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A student of the Ph.D. Programme in Experimental Biology and Biomedicine, Centro de Neurociências e Biologia Celular de Coimbra, University of Coimbra.

² To whom correspondence should be addressed: Tel.: 351-239-480-209; Fax: 351-239-480-208; E-mail: cbduarte{at}ci.uc.pt.

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