Regulating Quantal Size of Neurotransmitter Release through a GPCR Voltage Sensor

Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

Download Full-text

Reliable evaluation of the quantal determinants of synaptic efficacy using Bayesian analysis

Journal of Neurophysiology ◽

10.1152/jn.00528.2012 ◽

2013 ◽

Vol 109 (2) ◽

pp. 603-620 ◽

Cited By ~ 17

Author(s):

G. S. Bhumbra ◽

M. Beato

Keyword(s):

Neurotransmitter Release ◽

Fluctuation Analysis ◽

Small Data ◽

Data Sets ◽

Release Probability ◽

Postsynaptic Receptors ◽

Quantal Size ◽

Electrophysiological Recordings ◽

Small Data Sets ◽

The Central Nervous System

Communication between neurones in the central nervous system depends on synaptic transmission. The efficacy of synapses is determined by pre- and postsynaptic factors that can be characterized using quantal parameters such as the probability of neurotransmitter release, number of release sites, and quantal size. Existing methods of estimating the quantal parameters based on multiple probability fluctuation analysis (MPFA) are limited by their requirement for long recordings to acquire substantial data sets. We therefore devised an algorithm, termed Bayesian Quantal Analysis (BQA), that can yield accurate estimates of the quantal parameters from data sets of as small a size as 60 observations for each of only 2 conditions of release probability. Computer simulations are used to compare its performance in accuracy with that of MPFA, while varying the number of observations and the simulated range in release probability. We challenge BQA with realistic complexities characteristic of complex synapses, such as increases in the intra- or intersite variances, and heterogeneity in release probabilities. Finally, we validate the method using experimental data obtained from electrophysiological recordings to show that the effect of an antagonist on postsynaptic receptors is correctly characterized by BQA by a specific reduction in the estimates of quantal size. Since BQA routinely yields reliable estimates of the quantal parameters from small data sets, it is ideally suited to identify the locus of synaptic plasticity for experiments in which repeated manipulations of the recording environment are unfeasible.

Download Full-text

A novel and specific regulator of neuronal V-ATPase in Drosophila

10.1101/2021.02.08.430253 ◽

2021 ◽

Author(s):

Amina Dulac ◽

Abdul-Raouf Issa ◽

Jun Sun ◽

Giorgio Matassi ◽

Baya Chérif-Zahar ◽

...

Keyword(s):

Neuromuscular Junction ◽

Proton Pump ◽

Sequence Homology ◽

Neurotransmitter Release ◽

Synaptic Vesicles ◽

Eukaryotic Cells ◽

Its Sequence ◽

Quantal Size ◽

Atpase Subunits ◽

Enzymatic Complex

AbstractThe V-ATPase is a highly conserved enzymatic complex that ensures appropriate levels of organelle acidification in virtually all eukaryotic cells. While the general mechanisms of this proton pump have been well studied, little is known about the specific regulations of neuronal V-ATPase. Here, we studied CG31030, a previously uncharacterized Drosophila protein predicted from its sequence homology to be part of the V-ATPase family. We found that this protein is essential and apparently specifically expressed in neurons, where it is addressed to synaptic terminals. We observed that CG31030 co-immunoprecipitated with V-ATPase subunits, in particular with ATP6AP2, and that synaptic vesicles of larval motoneurons were not properly acidified in CG31030 knockdown context. This defect was associated with a decrease in quantal size at the neuromuscular junction, severe locomotor impairments and shortened lifespan. Overall, our data provide evidence that CG31030 is a specific regulator of neuronal V-ATPase that is required for synaptic vesicle acidification and neurotransmitter release.

Download Full-text

Central cholinergic synaptic vesicle loading obeys the set-point model in Drosophila

Journal of Neurophysiology ◽

10.1152/jn.01053.2015 ◽

2016 ◽

Vol 115 (2) ◽

pp. 843-850 ◽

Cited By ~ 4

Author(s):

Francesca Cash ◽

Samuel W. Vernon ◽

Pauline Phelan ◽

Jim Goodchild ◽

Richard A. Baines

Keyword(s):

Synaptic Vesicle ◽

Neurotransmitter Release ◽

Point Model ◽

Set Point ◽

Cholinergic Interneurons ◽

Quantal Size ◽

Cholinergic Synapses ◽

Steady State Model ◽

Central Synapses ◽

Polyq Domain

Experimental evidence shows that neurotransmitter release, from presynaptic terminals, can be regulated by altering transmitter load per synaptic vesicle (SV) and/or through change in the probability of vesicle release. The vesicular acetylcholine transporter (VAChT) loads acetylcholine into SVs at cholinergic synapses. We investigated how the VAChT affects SV content and release frequency at central synapses in Drosophila melanogaster by using an insecticidal compound, 5Cl-CASPP, to block VAChT and by transgenic overexpression of VAChT in cholinergic interneurons. Decreasing VAChT activity produces a decrease in spontaneous SV release with no change to quantal size and no decrease in the number of vesicles at the active zone. This suggests that many vesicles are lacking in neurotransmitter. Overexpression of VAChT leads to increased frequency of SV release, but again with no change in quantal size or vesicle number. This indicates that loading of central cholinergic SVs obeys the “set-point” model, rather than the “steady-state” model that better describes loading at the vertebrate neuromuscular junction. However, we show that expression of a VAChT polymorphism lacking one glutamine residue in a COOH-terminal polyQ domain leads to increased spontaneous SV release and increased quantal size. This effect spotlights the poly-glutamine domain as potentially being important for sensing the level of neurotransmitter in cholinergic SVs.

Download Full-text