The Role of Neurotrophins in Neurotransmitter Release

Abstract

The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activitydependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by "fine-tuning" synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during highfrequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as "kiss-and-run." By modulating Ca 2+ microdomains associated with voltage-gated Ca 2+ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system. KeywordsBDNF; Docked vesicles; Fusion pore; Hippocampus; mEPSC; Poisson stimulation; Quantal release; SNARE proteins; Synaptic vesicles; TrkB; Voltage-gated Ca 2+ channels Experience-dependent changes in the efficacy of fast synaptic transmission are thought to be a mechanism by which an organism adapts and changes in response to interactions with its environment. How, where, and under what conditions these changes in synaptic strength occur has been under intense speculation for more than half a century. Since the development of Katz's seminal quantal theory of neurotransmitter release (Katz 1969), a host of molecules have been evaluated for their ability to modulate synaptic strength by enhancing quantal neurotransmitter release. Advances in our current knowledge and technology have permitted for more precise delineation of pre-and postsynaptic sites of action with regard to enhanced synaptic transmission, although these sites are not always mutually exclusive. Recently, neurotrophins (NT) have emerged as candidates to mediate those modulatory actions at synapses because of their pronounced effects on quantal neurotransmitter release in both the central and peripheral nervous system. The mammalian NTs, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4/5 (NT-4/5) have all been shown to be essential for neuronal viability and differentiation, as well as synaptic plasticity in various brain regions ). The implications of activity-dependent bidirectional release and signaling at synapses make NTs ideally suited to modify the strength...

BDNF enhances dendritic Ca2+ signals evoked by coincident EPSPs and back-propagating action potentials in CA1 pyramidal neurons

“…These larger spines with wider necks are thought to represent spines that acquired AMPA receptors immediately after the induction of long-term potentiation (Matsuzaki et al, 2001;Kasai et al, 2003), and thus enhance spine-dendrite coupling leading to widespread dendritic Ca 2+ signaling during excitatory synaptic transmission (Noguchi et al, 2005). Together with the morphological effects of BDNF on presynaptic terminals (Tyler et al, 2002b) and postsynaptic spine growth and form Pozzo-Miller, 2001, 2003;Alonso et al, 2004), we propose that the larger Ca 2+ signals in spiny dendrites during coincident pre-and postsynaptic activation represent a physiological consequence of the structural BDNF actions at hippocampal synapses. The combination of these structural and physiological effects in the hippocampus may underlie the role of BDNF in the consolidation of synaptic plasticity and hippocampal-dependent learning and memory (Tyler et al, 2002a;Bramham and Messaoudi, 2005).…”

From Acquisition to Consolidation: On the Role of Brain-Derived Neurotrophic Factor Signaling in Hippocampal-Dependent Learning

“…Whereas there is extensive evidence of the modulatory effects of BDNF/TrkB signaling on presynaptic plasticity (for review, see Tyler et al 2002), BDNF has also been shown to have intriguing postsynaptic effects. Changes in postsynaptic responsiveness to presynaptic glutamate release may include enhanced glutamate receptor function, as well as modulation of voltage-gated ion channels.…”

“…Even though BDNF has been repeatedly hypothesized to play a role in learning and memory, evidence of such a role in behaving animals is only beginning to emerge. The extensive literature on the role of NTs in synaptic plasticity, including neurotransmitter release and intracellular signaling cascades, has been reviewed in recent articles (Segal and Greenberg 1996;Schinder and Poo 2000;Thoenen 2000;Poo 2001;Tyler et al 2002). The aims of the present review are to examine the behavioral evidence supporting the involvement of BDNF-triggered intracellular cascades in hippocampal-mediated learning and memory, as well as to evaluate the evidence showing the involvement of those same signaling cascades in forms of hippocampal excitatory synaptic plasticity thought to underlie mechanistically some forms of learning and memory.…”

Correlated network activity enhances synaptic efficacy via BDNF and the ERK pathway at immature CA3–CA1 connections in the hippocampus

“…Upon phosphorylation, ERK is translocated into the nucleus, where it activates the transcription factor cAMP response element-binding protein, thus contributing to the persistent modifications in synaptic efficacy (28)(29)(30)(31). To assess the role of ERK in synaptic potentiation, the pairing procedure was performed in the presence of the ERK inhibitors U0126 and PD98059.…”