Control of extracellular cleavage of ProBDNF by high frequency neuronal activity

Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1267-72. doi: 10.1073/pnas.0807322106. Epub 2009 Jan 15.

Abstract

Pro- and mature neurotrophins often elicit opposing biological effects. For example, mature brain-derived neurotrophic factor (mBDNF) is critical for long-term potentiation induced by high-frequency stimulation, whereas proBDNF facilitate long-term depression induced by low-frequency stimulation. Because mBDNF is derived from proBDNF by endoproteolytic cleavage, mechanisms regulating the cleavage of proBDNF may control the direction of BDNF regulation. Using methods that selectively detect proBDNF or mBDNF, we show that low-frequency stimulation induced predominant proBDNF secretion in cultured hippocampal neurons. In contrast, high-frequency stimulation preferentially increased extracellular mBDNF. Inhibition of extracellular, but not intracellular cleavage of proBDNF greatly reduced high-frequency stimulation-induced extracellular mBDNF. Moreover, high-frequency, but not low-frequency stimulation selectively induced the secretion of tissue plasminogen activator, a key protease involved in extracellular proBDNF to mBDNF conversion. Thus, high-frequency neuronal activity controls the ratio of extracellular proBDNF/mBDNF by regulating the secretion of extracellular proteases. Our study demonstrates activity-dependent control of extracellular proteolytic cleavage of a secretory protein, and reveals an important mechanism that controls diametrically opposed functions of BDNF isoforms.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Electric Stimulation
  • Extracellular Space / metabolism*
  • Intracellular Space / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Neurons / physiology*
  • Protein Isoforms / metabolism
  • Protein Precursors / metabolism
  • Rats
  • Tissue Plasminogen Activator / deficiency
  • Tissue Plasminogen Activator / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Protein Isoforms
  • Protein Precursors
  • Tissue Plasminogen Activator