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Review
. 2002 Dec;8(6):524-31.
doi: 10.1177/1073858402238511.

The role of neurotrophins in neurotransmitter release

William J Tyler  1 , Stephen P Perrett, Lucas D Pozzo-Miller
Affiliations
Review

The role of neurotrophins in neurotransmitter release

William J Tyler et al. Neuroscientist. 2002 Dec.

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 activity-dependent 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 high-frequency 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 Ca2+ microdomains associated with voltage-gated Ca2+ 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.

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Figures

Fig. 1
Fig. 1
BDNF increases the frequency of AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude. Whole-cell voltage-clamp recordings were performed in CA1 pyramidal neurons from hippocampal slice cultures treated for 5 days in vitro with serum-free control media (left A, B, and C), or BDNF (250 ng/ml; right A, B, and C). A, Representative unitary AMPA-mediated mEPSCs. BDNF treatment did not affect the kinetics or amplitude of AMPA mEPSCs. B, Representative continuous records of membrane currents showing AMPA mEPSC events from control- (left) or BDNF- (right) treated slice cultures. C, Frequency histogram distributions (5pA bins) of events recorded from the control- (left) and BDNF- (right) treated cell in 10- to 30-s epochs. Total number of events recorded and frequency of mEPSCs are shown above each frequency histogram distribution. D, Cumulative probability distribution of interevent (mEPSC) intervals. E, cumulative probability distribution of mEPSC amplitude from six cells each obtained from control (open circles) and BDNF (filled circles) treated hippocampal slice cultures. (Modified from Tyler and Pozzo-Miller 2001.)
Fig. 2
Fig. 2
BDNF increases the number of docked synaptic vesicles at the active zones of CA3-CA1 excitatory synapses. A, Histogram plot of the number of docked synaptic vesicles per μm of active zone. Data are illustrated as mean ± SEM (control n = 98 synapses, BDNF n = 101 synapses; asterisk indicates P < 0.05). Interestingly, the effect on DV was observed in the absence of an observed effect on the total number of reserve pool vesicles. B, Representative electron micrographs of synapses on dendritic spines within CA1 stratum radiatum from serum-free control (top), and slice cultures treated with BDNF (250 ng/ml; bottom) for 5 days in vitro. Morphologically docked synaptic vesicles are indicated with a white circle superimposed with a black circle. (Modified from Tyler and Pozzo-Miller 2001.)
Fig. 3
Fig. 3
Stimulation with Poisson-distributed intervals induces much less synaptic depression than stimulation with constant intervals. Representative examples are shown in which synaptic depression was induced by a 5 Hz stimulus train (3 min, 900 stimuli, initiated at time 0) with either Poisson-distributed intervals (A; C, open circles) or constant intervals (B; C, filled circles) between stimuli. Stimulation at constant intervals of 10 s was delivered before each train to determine the baseline excitatory postsynaptic potential (EPSP) amplitude and following each train to assess the rate of recovery from synaptic depression. A, Average of 10 EPSP traces taken (from left to right) immediately preceding, at the beginning, and at the end of the 5 Hz Poisson train. B, Average of 10 traces taken (from left to right) immediately preceding, at the beginning, and at the end of the 5 Hz constant train. Note that there is effectively a failure of synaptic transmission by the end of the train. C, Plot of the peak amplitudes of EPSPs relative to baseline during and immediately following Poisson (open circles) and constant (filled circles) 5 Hz stimulus trains. During Poisson stimulation, EPSP amplitudes quickly declined during the first 30 s of the train before stabilizing at ∼50% of baseline amplitude. During constant stimulation, EPSP amplitudes declined throughout the first 2 min of the train before stabilizing at ∼10% of baseline amplitude. D, Following the Poisson train synaptic strength recovered to baseline within 20 sec, whereas it took 480 s for complete recovery from synaptic depression following the constant train. Dashed lines denote average baseline EPSP amplitude. Scale bars = 2 mV, 10 sec (S. P. Perrett and M. J. Friedlander, unpublished observations).
Fig. 4
Fig. 4
Working model for the mechanism by which NT-Trk signaling enhances quantal neurotransmitter release. The model depicted is an oversimplified illustration of mechanisms known to play a fundamental role in neurotransmitter release at fast chemical synapses. The upper panel illustrates SNARE-mediated synaptic vesicles docking at the presynaptic active zone. The Ca2+ signal is illustrated as an isoconcentration surface depicting the Ca2+ microdomain that triggers vesicle fusion, and neurotransmitter release (after Simon and Llinás 1985). The lower panel depicts the same release site after activation of the signaling cascades triggered by NT binding to Trk receptors. The docked vesicle at far right presents a cutaway view for display purposes. This illustration shows an increase in both v-SNARE and t-SNARE proteins, an increase in the number of DVs, and the occurrence of overlapping Ca2+ microdomains. Following NT-Trk signaling, an increase in the SNARE proteins associated with synaptic vesicle mobilization and targeting increases the number of docking sites, as well as the probability of a vesicle occupying that site. Direct NT modulation of Ca2+ channels responsible for the appearance of a Ca2+ microdomain results in the higher Ca2+ levels necessary to switch from the conventional slow mode of vesicle retrieval to the faster and more reliable “kiss and run” endocytotic pathway.
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