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The Journal of Neuroscience, July 8, 2009, 29(27):8688-8697; doi:10.1523/JNEUROSCI.6078-08.2009

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Development/Plasticity/Repair
Positive AMPA Receptor Modulation Rapidly Stimulates BDNF Release and Increases Dendritic mRNA Translation

Hussam Jourdi,^1 * Yu-Tien Hsu,^1 * Miou Zhou,^1 * Qingyu Qin,² Xiaoning Bi,² and Michel Baudry¹

¹Neurobiology, University of Southern California, Los Angeles, California 90089, and ²Western University of Health Sciences, Pomona, California 91766

Correspondence should be addressed to Michel Baudry, University of Southern California, Los Angeles, CA 90089-2520. Email: baudry{at}usc.edu

Brain-derived neurotrophic factor (BDNF) stimulates local dendritic mRNA translation and is involved in formation and consolidation of memory. 2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan-10-one (CX614), one of the best-studied positive AMPA receptor modulators (also known as ampakines), increases BDNF mRNA and protein and facilitates long-term potentiation (LTP) induction. Several other ampakines also improve performance in various behavioral and learning tasks. Since local dendritic protein synthesis has been implicated in LTP stabilization and in memory consolidation, this study investigated whether CX614 could influence synaptic plasticity by upregulating dendritic protein translation. CX614 treatment of primary neuronal cultures and acute hippocampal slices rapidly activated the translation machinery and increased local dendritic protein synthesis. CX614-induced activation of translation was blocked by K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], CNQX, APV, and TTX, and was inhibited in the presence of an extracellular BDNF scavenger, TrkB-Fc. The acute effect of CX614 on translation was mediated by increased BDNF release as demonstrated with a BDNF scavenging assay using TrkB-Fc during CX614 treatment of cultured primary neurons and was blocked by nifedipine, ryanodine, and lack of extracellular Ca²⁺ in acute hippocampal slices. Finally, CX614, like BDNF, rapidly increased dendritic translation of an exogenous translation reporter. Together, our results demonstrate that positive modulation of AMPA receptors rapidly stimulates dendritic translation, an effect mediated by BDNF secretion and TrkB receptor activation. They also suggest that increased BDNF secretion and stimulation of local protein synthesis contribute to the effects of ampakines on synaptic plasticity.

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Received Dec. 22, 2008; revised May 18, 2009; accepted May 19, 2009.

Correspondence should be addressed to Michel Baudry, University of Southern California, Los Angeles, CA 90089-2520. Email: baudry{at}usc.edu

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