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J. Biol. Chem., Vol. 283, Issue 30, 21242-21250, July 25, 2008

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Brain-derived Neurotrophic Factor-Tropomyosin-related Kinase B Signaling Contributes to Activity-dependent Changes in Synaptic Proteins^*

From the Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

The ability of synapses to undergo changes in structure and function in response to alterations of neuronal activity is an essential property of neural circuits. One way that this is achieved is through global changes in the molecular composition of the synapse; however, it is not clear how these changes are coupled to the dynamics of neuronal activity. Here we found that, in cultured rat cortical neurons, bidirectional changes of neuronal activity led to corresponding alterations in the expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor tropomyosin-related kinase B (TrkB), as well as in the level of synaptic proteins. Exogenous BDNF reversed changes in synaptic proteins induced by chronic activity blockade, while inhibiting Trk kinase activity or depleting endogenous BDNF abolished the concentration changes induced by chronic activity elevation. Both tetrodotoxin and bicuculline had significant, but opposite, effects on synaptic protein ubiquitination in a time-dependent manner. Furthermore, exogenous BDNF was sufficient to increase ubiquitination of synaptic proteins, whereas scavenging endogenous BDNF or inhibiting Trk kinase activity prevented the ubiquitination of synaptic proteins induced by chronic elevation of neuronal activity. Inhibiting the proteasome or blocking protein polyubiquitination mimicked the effect of tetrodotoxin on the levels of synaptic proteins and canceled the effects of BDNF. Our study indicates that BDNF-TrkB signaling acts upstream of the ubiquitin proteasome system, linking neuronal activity to protein turnover at the synapse.

Received for publication, January 11, 2008 , and in revised form, April 23, 2008.

^* This work was supported by grants from the National Basic Research Program of China (2006CB806600), the Key State Research Program of China (2006CB943900), the National "863" Hi-tech Research and Development Program (2006AA02Z166), the Innovative Research Group of The National Natural Science Foundation of China (30721004), and the Chinese Academy of Sciences (KSCX2-YW-R-099). 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 To whom correspondence should be addressed: Inst. of Neuroscience, 320 Yueyang Rd., Shanghai 200031, China. Tel.: 86-21-54921720; Fax: 86-21-5492-1735; E-mail: xiongzhiqi{at}ion.ac.cn.

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