Role Of Short-term Synaptic Plasticity Research Articles

Delineating the Molecular Basis of the Calmodulin‒bMunc13-2 Interaction by Cross-Linking/Mass Spectrometry-Evidence for a Novel CaM Binding Motif in bMunc13-2.

Exploring the interactions between the Ca2+ binding protein calmodulin (CaM) and its target proteins remains a challenging task. Members of the Munc13 protein family play an essential role in short-term synaptic plasticity, modulated via the interaction with CaM at the presynaptic compartment. In this study, we focus on the bMunc13-2 isoform expressed in the brain, as strong changes in synaptic transmission were observed upon its mutagenesis or deletion. The CaM–bMunc13-2 interaction was previously characterized at the molecular level using short bMunc13-2-derived peptides only, revealing a classical 1–5–10 CaM binding motif. Using larger protein constructs, we have now identified for the first time a novel and unique CaM binding site in bMunc13-2 that contains an N-terminal extension of a classical 1–5–10 CaM binding motif. We characterize this motif using a range of biochemical and biophysical methods and highlight its importance for the CaM–bMunc13-2 interaction.

Novel Distinctive Roles of Docking Proteins in Short-term Synaptic Plasticity of Frog Neuromuscular Transmission Revealed by Botulinum Neurotoxins

Short-term synaptic plasticity (SSP) is a basic mechanism for temporal processing of neural information in synaptic transmission. Facilitation, the fastest component of SSP, has been extensively investigated with regard to Ca2+ signaling and other relevant substances. However, systematic analyses on the slower components of SSP, originated by Magleby and Zengel, have remained stagnant for decades, as few chemicals directly modifying these slower components have been identified. In combination with refined experimental protocols designed to study the stimulation frequency-dependence of SSP and botulinum neurotoxins A and C (BoNT-A and BoNT-C), we investigated SSP of frog neuromuscular transmission to clarify the roles of synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin, SNARE proteins exclusively participating in vesicular events including docking, priming and exocytosis. We found that BoNT-A treatment eliminated slow potentiation, and BoNT-C poisoning abolished intermediate augmentation, two components of SSP. Fast facilitation was maintained after double poisoning with BoNT-A and -C, but the postsynaptic response became biphasic. A novel depression, termed repression, emerged by double poisoning. Repression was different from depletion because it developed even at a low-frequency stimulation of 1 Hz. We conclude that SNAP-25 and syntaxin not only play roles as cooperative exocytotic machinery, but also have roles in SSP.

Diverse Ensembles of Inhibitory Interneurons

In this issue of Neuron, Karnani etal. (2016) show that ensembles of specific types of inhibitory interneurons generate coordinated activity in mouse visual cortex. They also describe chemical and electrical synaptic mechanisms that may enable diverse interneuron ensembles to function as distinct operational units.

Calcium-Dependent PKC Isoforms Have Specialized Roles in Short-Term Synaptic Plasticity

Posttetanic potentiation (PTP) is a widely observed form of short-term plasticity lasting for tens of seconds after high-frequency stimulation. Here we show that although protein kinase C (PKC) mediates PTP at the calyx of Held synapse in the auditory brainstem before and after hearing onset, PTP is produced primarily by an increased probability of release (p) before hearing onset, and by an increased readily releasable pool of vesicles (RRP) thereafter. We find that these mechanistic differences, which have distinct functional consequences, reflect unexpected differential actions of closely related calcium-dependent PKC isoforms. Prior to hearing onset, when PKCγ and PKCβ are both present, PKCγ mediates PTP by increasing p and partially suppressing PKCβ actions. After hearing onset, PKCγ is absent and PKCβ produces PTP by increasing RRP. In hearing animals, virally expressed PKCγ overrides PKCβ to produce PTP by increasing p. Thus, two similar PKC isoforms mediate PTP in distinctly different ways.

Probabilistic inference of synaptic dynamics in neocortical microcircuits

Short-term synaptic plasticity (STP) is highly varied across brain area, cortical layer, cell type, and developmental stage (Reyes & Sakmann 1999). This variability is probably not coincidental and since synaptic dynamics shape neural computations, it suggests an important role of STP in neural information processing (Abbott & Regehr 2004). Therefore, an accurate description of STP is a key step towards a comprehensive understanding of neural systems. Many phenomenological STP models have been developed (Markram et al. 1998), but they have typically been fitted to experimental data using least-mean-square methods. With the Tsodyks-Markram model, we find that for typical synaptic dynamics such fitting procedures may give erratic outcomes. A Bayesian formulation based on a Markov Chain Monte Carlo method was introduced as a solution. This formulation provides the posterior distribution over the model parameters given the data statistics. We discovered that standard STP electrophysiology protocols yielded wide distributions over some model parameters. Based on this result we propose experimental protocols to more accurately determine model parameters. Next, the model parameters were inferred using experimental data from three different neocortical excitatory connection types: Pyramidal Cell-Pyramidal Cell (PC-PC), Pyramidal Cell-Basket Cell (PC-BC) and Pyramidal Cell-Martinotti Cell (PC-MC), (see Figure ​Figure1).1). This disclosed connection-specific distributions, which we used to classify synapses. This approach to determining connection-specific synaptic dynamics provides a more comprehensive representation of STP and unveils novel features from existing data. Figure 1 Posterior distributions of STP parameters from experimental data from visual cortex layer-5. (A) Sample experimental STP traces are shown for PC-PC (red), PC-BC (green), and for PC-MC (blue) connections. (B) Marginalized posterior distributions obtained ...

A role of short-term synaptic plasticity in extracting velocity information of target in echolocating bats

A role of short-term synaptic plasticity in extracting velocity information of target in echolocating bats

Effect of Short-Term Synaptic Plasticity on Correlated firing in Feedback Networks

The firing activity of a neuronal population is correlated, which has been linked to information coding and exchanging. Short-term synaptic plasticity allows synapses to increase (facilitate) or decrease (depress) over a wide range of time scales. It is critical to understand the characteristics and mechanisms of the correlated firing and the role of short-term synaptic plasticity in regulating firing activity. The short-term synaptic depression and facilitation are examined at the synapses in the inhibitory feedback loop of feedback neural networks. Numerical simulations reveal that the modulation of the correlated firing by dynamics of depression and facilitation is due to their effects on the synaptic strength. By varying synaptic time constants, the enhancement in either firing rate or intensity of oscillations can improve the correlated firing. Our study thus provides a general computational analysis of the sequential interaction of short-term plasticity with neuronal firing.

Computational role of short-term synaptic plasticity in the neocortex

Computational role of short-term synaptic plasticity in the neocortex

A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity?

alpha-RIMs and Munc13s are active zone proteins that control priming of synaptic vesicles to a readily releasable state, and interact with each other via their N-terminal sequences. The alpha-RIM N-terminal sequence also binds to Rab3s (small synaptic vesicle GTPases), an interaction that regulates presynaptic plasticity. We now demonstrate that alpha-RIMs contain adjacent but separate Munc13- and Rab3-binding sites, allowing formation of a tripartite Rab3/RIM/Munc13 complex. Munc13 binding is mediated by the alpha-RIM zinc-finger domain. Elucidation of the three-dimensional structure of this domain by NMR spectroscopy facilitated the design of a mutation that abolishes alpha-RIM/Munc13 binding. Selective disruption of this interaction in the calyx of Held synapse decreased the size of the readily releasable vesicle pool. Our data suggest that the ternary Rab3/RIM/Munc13 interaction approximates synaptic vesicles to the priming machinery, providing a substrate for presynaptic plasticity. The modular architecture of alpha-RIMs, with nested binding sites for Rab3 and other targets, may be a general feature of Rab effectors that share homology with the alpha-RIM N-terminal sequence.

Group III metabotropic glutamate receptors as autoreceptors in the cerebellar cortex

1. Group III metabotropic glutamate receptors (mGluRs) of the subtype 4a are localized within presynaptic active zones of cerebellar parallel fibre (PF)-Purkinje cell (PC) synapses. In order to investigate the conditions necessary for group III mGluR autoreceptor-activation by synaptically released glutamate, we characterized the effects of selective agonists and antagonists on excitatory postsynaptic currents (EPSCs) evoked by several distinct PF stimulation patterns. 2. The group III mGluR-selective agonist L-AP4 depressed evoked EPSCs at PF-PC synapses in rat brain slices with an EC(50) of 2.4 microM and maximum inhibition of 80%. This L-AP4-induced depression was antagonized by the group III mGluR-selective antagonist MSOP with an estimated equilibrium dissaciation constant of 12.5 microM. 3. Paired-pulse or four-pulse PF stimulations did not activate presynaptic group III mGluRs as revealed by the lack of effect of 1 mM MSOP on relative test EPSC amplitudes with latencies of 250-500 ms. The potentiation of a test EPSC evoked 200-500 ms after a short tetanic burst (100 Hz for 60 ms), was also unchanged in the presence of MSOP. 4. Endogenous autoreceptor-activation was revealed only during prolonged stimulation trains (10 Hz for 4.4 s), where, in the presence of 1 mM MSOP, the EPSC amplitudes were enhanced by 15%. 5. These observations support an autoreceptor function of group III mGluRs and a role in short-term synaptic plasticity at PF synapses. However, the low to moderate activation levels observed, despite the close spatial relation with glutamate release sites, suggests that additional mechanisms regulate receptor activation.