BDNF INDUCES WIDESPREAD CHANGES IN SYNAPTIC PROTEIN CONTENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The brain-derived neurotrophic factor (BDNF) plays an important role in neuronal development, and in the formation and plasticity of synaptic connections. These effects of BDNF are at least partially due to the ability of the neurotrophin to increase protein synthesis both globally and locally. However, only a few proteins have been shown to be up-regulated at the synapse by BDNF. Using multi-dimensional protein identification technology (MudPIT) and relative quantification by spectra counting, we found that several hundred proteins are up-regulated in a synaptoneurosome preparation derived from cultured cortical neurons after treatment with BDNF. These proteins fall into diverse functional categories, including those involved in synaptic vesicle formation and movement, maintenance or remodeling of synaptic structure, mRNA processing, transcription and translation. A number of translation factors, ribosomal proteins, and tRNA synthetases were rapidly up-regulated by BDNF. This up-regulation of translation components was sensitive to protein synthesis inhibitors, and dependent on the activation of the mammalian target of rapamycin (mTOR), a regulator of cap-dependent mRNA translation. The presence of a subset of these proteins and their mRNAs in neuronal processes was corroborated by immunocytochemistry and in situ hybridization, and their up-regulation was confirmed by Western blotting. The data demonstrate that BDNF increases the synthesis of a wide variety of synaptic proteins and suggest that BDNF enhances the translational capacity of synapses.