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

Volkmar Leßmann,Elke Edelmann,Sergio M. G. Solinas,Michele Migliore

doi:10.1371/journal.pcbi.1006975

Abstract

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.

Highlights

Brain-Derived Neurotrophic Factor (BDNF) is a member of the protein family of mammalian neurotrophins, further comprising nerve growth factor, neurotrophin 3 and neurotrophin 4/5
Storing memory traces in the brain is essential for learning and memory formation, and it occurs through synaptic plasticity processes
Timing-dependent Long-Term Potentiation (t-LTP) is a physiologically relevant type of synaptic plasticity that results from the repeated sequential firing of action potentials (APs) in pre- and postsynaptic neurons

Summary

Introduction

Brain-Derived Neurotrophic Factor (BDNF) is a member of the protein family of mammalian neurotrophins, further comprising nerve growth factor, neurotrophin 3 and neurotrophin 4/5. A wealth of data has been accumulated on the many roles of BDNF in regulating synaptic plasticity at glutamatergic and GABAergic synapses, e.g. in hippocampus, neocortex, amygdala, and cerebellum, unraveling signaling pathways of unprecedented complexity [1,6,7,8,9,10]. Despite this well-established role of BDNF as a central activitydependent mediator (i.e. switching on biochemical pathways that induce and maintain enhanced synaptic transmission [11,12,13]) and modulator (i.e., facilitating synaptic changes that are mediated by other signaling pathways [3,14,15,16,17]) of synaptic plasticity, the interplay between intra- and extracellular signaling pathways [18,19] that regulate and fine-tune BDNFdependent synaptic changes is not well understood. All three BDNF species are thought to be assembled into secretory vesicles that are transported to the plasma membrane in soma, dendrites, and axons, where they release their content via Ca2+-dependent exocytosis [20]

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