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BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia

Nature Neuroscience volume 7, pages 48–55 (2004)Cite this article

Abstract

Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.

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Figure 1: Intermittent hypoxia elicits pLTF and increased BDNF synthesis in ventral spinal segments associated with the phrenic motor nucleus.
Figure 2: Regulation of ventral cervical BDNF following intermittent hypoxia.
Figure 3: Intrathecal BDNF facilitates phrenic motor output.
Figure 4: BDNF siRNA reduced BDNF mRNA in vitro as well as hypoxia-induced BDNF synthesis in vivo.
Figure 5: BDNF siRNA and Trk receptor inhibition with K252a block pLTF.

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Acknowledgements

These experiments were supported by National Institutes of Health (NIH) grant HL 65383. T.L.B.-H. and R.W.B. were supported by NIH Training Grant HL 07654. D.D.F. was supported by the Parker B. Francis Foundation. F.J.G. was supported by a Christopher Reeve Paralysis Foundation Fellowship (GA1-0305-2). We thank B. Hodgeman for technical assistance.

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Authors and Affiliations

  1. Department of Comparative Biosciences, University of Wisconsin, Madison, 53706, Wisconsin, USA

    Tracy L Baker-Herman, David D Fuller, Ryan W Bavis, Andrea G Zabka, Francis J Golder, Nicholas J Doperalski, Rebecca A Johnson, Jyoti J Watters & Gordon S Mitchell

  2. Center for Neuroscience, University of Wisconsin, Madison, 53706, Wisconsin, USA

    Jyoti J Watters & Gordon S Mitchell

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Baker-Herman, T., Fuller, D., Bavis, R. et al. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci 7, 48–55 (2004). https://doi.org/10.1038/nn1166

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