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The Journal of Neuroscience, June 13, 2007, 27(24):6417-6427; doi:10.1523/JNEUROSCI.0690-07.2007

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Development/Plasticity/Repair
Brain-Derived Neurotrophic Factor Regulates Cholesterol Metabolism for Synapse Development

Shingo Suzuki,^1,2 Kazuyuki Kiyosue,³ Shunsuke Hazama,^1,4 Akihiko Ogura,⁴ Megumi Kashihara,¹ Tomoko Hara,^1,2 Hisatsugu Koshimizu,¹ and Masami Kojima^1,2

¹Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka 563-8577, Japan, ²Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, ³Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba 305-8566, Japan, and ⁴Department of Neuroscience, Osaka University Graduate School of Frontier Biosciences, Toyonaka, Osaka 560-0043, Japan

Correspondence should be addressed to Masami Kojima, Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan. Email: m-kojima{at}aist.go.jp

Brain-derived neurotrophic factor (BDNF) exerts multiple biological functions in the CNS. Although BDNF can control transcription and protein synthesis, it still remains open to question whether BDNF regulates lipid biosynthesis. Here we show that BDNF elicits cholesterol biosynthesis in cultured cortical and hippocampal neurons. Importantly, BDNF elicited cholesterol synthesis in neurons, but not in glial cells. Quantitative reverse transcriptase-PCR revealed that BDNF stimulated the transcription of enzymes in the cholesterol biosynthetic pathway. BDNF-induced cholesterol increases were blocked by specific inhibitors of cholesterol synthesis, mevastatin and zaragozic acid, suggesting that BDNF stimulates de novo synthesis of cholesterol rather than the incorporation of extracellular cholesterol. Because cholesterol is a major component of lipid rafts, we investigated whether BDNF would increase the cholesterol content in lipid rafts or nonraft membrane domains. Interestingly, the BDNF-mediated increase in cholesterol occurred in rafts, but not in nonrafts, suggesting that BDNF promotes the development of neuronal lipid rafts. Consistent with this notion, BDNF raised the level of the lipid raft marker protein caveolin-2 in rafts. Remarkably, BDNF increased the levels of presynaptic proteins in lipid rafts, but not in nonrafts. An electrophysiological study revealed that BDNF-dependent cholesterol biosynthesis plays an important role for the development of a readily releasable pool of synaptic vesicles. Together, these results suggest a novel role for BDNF in cholesterol metabolism and synapse development.

Key words: brain-derived neurotrophic factor; TrkB receptor; cholesterol; synapse development; lipid rafts; CNS neurons

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Received July 27, 2006; revised April 15, 2007; accepted May 2, 2007.

Correspondence should be addressed to Masami Kojima, Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan. Email: m-kojima{at}aist.go.jp

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