A kinetic model for Brain-Derived Neurotrophic Factor mediated spike timing-dependent LTP

PLoS Comput Biol. 2019 Apr 24;15(4):e1006975. doi: 10.1371/journal.pcbi.1006975. eCollection 2019 Apr.


Across the mammalian nervous system, neurotrophins control synaptic plasticity, neuromodulation, and neuronal growth. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is known to promote structural and functional synaptic plasticity in the hippocampus, the cerebral cortex, and many other brain areas. In recent years, a wealth of data has been accumulated revealing the paramount importance of BDNF for neuronal function. BDNF signaling gives rise to multiple complex signaling pathways that mediate neuronal survival and differentiation during development, and formation of new memories. These different roles of BDNF for neuronal function have essential consequences if BDNF signaling in the brain is reduced. Thus, BDNF knock-out mice or mice that are deficient in BDNF receptor signaling via TrkB and p75 receptors show deficits in neuronal development, synaptic plasticity, and memory formation. Accordingly, BDNF signaling dysfunctions are associated with many neurological and neurodegenerative conditions including Alzheimer's and Huntington's disease. However, despite the widespread implications of BDNF-dependent signaling in synaptic plasticity in healthy and pathological conditions, the interplay of the involved different biochemical pathways at the synaptic level remained mostly unknown. In this paper, we investigated the role of BDNF/TrkB signaling in spike-timing dependent plasticity (STDP) in rodent hippocampus CA1 pyramidal cells, by implementing the first subcellular model of BDNF regulated, spike timing-dependent long-term potentiation (t-LTP). The model is based on previously published experimental findings on STDP and accounts for the observed magnitude, time course, stimulation pattern and BDNF-dependence of t-LTP. It allows interpreting the main experimental findings concerning specific biomolecular processes, and it can be expanded to take into account more detailed biochemical reactions. The results point out a few predictions on how to enhance LTP induction in such a way to rescue or improve cognitive functions under pathological conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Computational Biology
  • Hippocampus / cytology
  • Long-Term Potentiation / physiology*
  • Male
  • Memory / physiology
  • Mice
  • Mice, Knockout
  • Models, Neurological*
  • Neuronal Plasticity / physiology
  • Neurons / physiology
  • Rats, Wistar
  • Signal Transduction / physiology


  • Bdnf protein, rat
  • Brain-Derived Neurotrophic Factor

Grant support

This work has been supported by the EU Joint Program–Neurodegenerative Disease Research (JPND) project CIRCPROT (jointly funded by BMBF, MIUR, and EU Horizon 2020 grant agreement no. 643417) and the Horizon 2020 Framework Programme for Research and Innovation under the Specific Grant Agreement 785907 (Human Brain Project SGA2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.