Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus

  1. Wolfram A. Gottschalk1,
  2. Hao Jiang3,
  3. Nicole Tartaglia1,4,
  4. Linyin Feng1,2,
  5. Alexander Figurov1, and
  6. Bai Lu1,5
  1. 1Unit on Synapse Development and Plasticity, National Institute of Child Health and Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland 20892-4480 USA, 2Shanghai Research Center of Life Sciences, and Shanghai Brain Research Institute, Chinese Academy of Sciences, Shanghai, China 200031, 3Section on Growth Factors, NICHD, and 4Howard Hughes Medical Institute– NIH Research Scholars Program, Bethesda, Maryland 20829-4480 USA

Abstract

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-γ (PLC-γ) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-γ. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-γ, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.

Footnotes

  • 5 Corresponding author.

    • Received March 26, 1999.
    • Accepted May 4, 1999.
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