Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses

Abstract

The protein brain-derived neurotrophic factor (BDNF) has been postulated to be a retrograde or paracrine synaptic messenger in long-term potentiation and other forms of activity-dependent synaptic plasticity. Although crucial for this concept, direct evidence for the activity-dependent synaptic release of BDNF is lacking. Here we investigate secretion of BDNF labelled with green¯uorescent protein (BDNF±GFP) by monitoring the changes in¯uores-cence intensity of dendritic BDNF±GFP vesicles at glutamatergic synaptic junctions of living hippocampal neurons. We show that high-frequency activation of glutamatergic synapses triggers the release of BDNF±GFP from synaptically localized secretory granules. This release depends on activation of postsynaptic ionotropic glutamate receptors and on postsynaptic Ca 2+ in¯ux. Release of BDNF±GFP is also observed from extrasynaptic dendritic vesicle clusters, suggesting that a possible spatial restriction of BDNF release to speci®c synaptic sites can only occur if the postsynaptic depolarization remains local. These results support the concept of BDNF being a synaptic messenger of activity-dependent synaptic plasticity, which is released from postsynaptic neurons.

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

“…At synapses, BDNF signaling enhances LTP, probably by cAMP-response-element-binding protein(CREB)-mediated gene expression (Ernfors et al, 2003). BDNF is also more potent in modulating active synapses (Boulanger and Poo, 1999) and as expected, its secretion occurs in active synapses (Hartmann et al, 2001;Kojima et al, 2001). In vivo BDNF infusion increases the formation of new granule cells in adult hippocampus (hilus) Figure 2 This figure depicts the molecular and biochemical events occurring in NGF-deprived hippocampal neurons, although the precise temporal sequence is only hypothesized on a timing schedule of different experiments.…”

Single-Cell Characterization of Retrograde Signaling by Brain-Derived Neurotrophic Factor

“…In experiments with GFP-tagged BDNF, it was shown that high-frequency electrical stimulation could elicit release of BDNF from glutamatergic synaptic junctions (Hartmann et al, 2001). This secretion could be blocked by AMPA and NMDA antagonists and was shown to require an extracellular calcium influx (Hartmann et al, 2001).…”

“…There are also numerous studies showing that BDNF can elicit rapid (within minutes) presynaptic changes in synaptic activity (Lessmann, 1998;Lu and Gottschalk, 2000). For these types of synaptic plasticity, it is known that action potential firing can evoke BDNF release (Balkowiec and Katz, 2000;Hartmann et al, 2001), but it is not known whether moderate depolarization, of the type observed early during development (Ben-Ari, 2002), is also capable of inducing BDNF release. Moreover, it has not been fully shown whether BDNF actually fulfills the conditions necessary to qualify as a retrograde signaling molecule (Fitzsimonds and Poo, 1998), particularly at the single-cell level (Alger, 2002).…”

Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression

“…BDNF is produced by neurons, particularly in the hippocampus and cortex. Neuronal activity, i.e., during encoding of information, stimulates BDNF gene transcription, transport of BDNF mRNA into dendritic spines, and BDNF protein release into the synaptic cleft (Hartmann et al 2001). BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.…”