The readily-releasable pool dynamically regulates multivesicular release

Vaden, Jada H.; Banumurthy, Gokulakrishna; Gusarevich, E. S.; Overstreet-Wadiche, Linda; Wadiche, Jacques I.

doi:10.7554/elife.47434

Cited by 48 publications

(44 citation statements)

References 94 publications

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“…Mitochondria boost local ATP generation and control Ca +2 levels which allow enhanced mobilization and recycling of synaptic vesicles for exocytosis, neurotransmitter release and for the generation of synaptic membrane potentials, specially under repetitive high-frequency firing 33 . Likewise, the presence of large vesicle pools and extensive and complex PSDs is associated with higher neurotransmitter release probabilities and synaptic efficacy 17, 18, 19, 35 and to the number and distribution of postsynaptic receptors 20, 22, 23 . The striking differences in these parameters between Po MC-L3/4 and S1-L5a boutons thus imply that the first may readily keep a high release probability at high-frequency firing rates, which is consistent with the observed capacity of MC Po synapses to transmit signals with higher efficacy and temporal acuity than Po S1 synapses 3, 16 .…”

Section: Discussionmentioning

confidence: 99%

Area-specific synapse structure in branched axons reveals a subcellular level of complexity in thalamocortical networks

Moreno

Porrero

Rollenhagen

et al. 2019

Preprint

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37Thalamocortical Posterior nucleus (Po) axons innervating the somatosensory (S1) and 38 motor (MC) vibrissal cortices are key links in the brain neuronal network that allows 39 rodents to explore the environment whisking with their motile vibrissae. Here, using 40 high-end 3D electron microscopy, we demonstrate massive differences between MC vs. 41 S1 Po synapses in a) bouton and active zone size; b) neurotransmitter vesicle pool size; 42 c) mitochondria distribution near synapses; and d) proportion of non-spinous dendrite 43contacts. These differences are as large, or bigger, than those between Po and 44 ventroposterior thalamic nucleus synapses in S1. Moreover, using single-axon 45 transfection labeling, we show that the structure of boutons in the MC vs. S1 branches 46 of individual Po axons is different. These structural differences parallel striking, 47recently-discovered divergences in functional efficacy and plasticity between S1 and 48 MC Po synapses, and overall reveal a new, subcellular level of thalamocortical circuit 49 complexity, unaccounted for in current models. 50 51 Introduction 52 53 Rodents explore their environment by rhythmically "whisking" with their motile facial 54 vibrissae. Time-dependent correlations between motor commands and vibrissal follicle 55 mechanoreceptor signals are used for inferring object position and texture. Such 56 computations are carried out in multilevel, closed-loop neuronal networks 57 encompassing the brainstem, thalamus and neocortex (reviewed in 1 ). 58Two thalamocortical pathways lay at the core of these loops: Ventral Posteromedial 59 thalamic nucleus (VPM) axons arborizing focally on L4 in the vibrissal "barrel" domain 60 of the primary somatosensory cortex (S1); and Posterior thalamic nucleus (Po) axons 61 arborizing mainly in L5a but also L1 of S1 2; 3 . Importantly, Po axons may target, in 62 addition, the motor cortex (MC) middle layers 3, 4, 5 (L5-L3). The VPM axons relay 63 time-locked mechanoreceptive single-whisker trigeminal signals, crucial for computing 64 object location. In turn, Po axons convey information mainly about timing/amplitude 65 differences between ongoing cortical outputs and multi-whisker sensory signals, which 66 may be important for computing whisker position 1, 6, 7 . Po cells are primarily driven by 67 heavy and highly effective L5 cortico-thalamic inputs, while ascending trigeminal 68 inputs to Po are sparser and largely modulatory in character 7, 8 . 69Activation of S1-L4 VPM synapses elicits large currents in cortical neurons 9; 10 and 70 drives their firing with low failure rates 11, 12 . VPM synapses are driven only by 71 ionotropic receptors, depress rapidly upon repetitive stimulation 9 and, after an early 72 postnatal period, show considerable resistance to sensory experience-dependent changes 73 13 . In contrast, synaptic potentials evoked in S1 by Po axons show slower rise and decay 74 times, and elicit smaller currents 10, 14 . The Po S1 synapses involve both ionotropic and 75 metabotropic glutamate conductances, sho...

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Section: Discussionmentioning

confidence: 99%

Area-specific synapse structure in branched axons reveals a subcellular level of complexity in thalamocortical networks

Moreno

Porrero

Rollenhagen

et al. 2019

Preprint

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“…Indeed, the RRPs are by 3-5-fold, the RPs by 2-fold and the resting pools by 2-fold larger than in rodent and non-human primate neocortex. It has been recently shown that the size of the RRP dynamically regulates multivesicular release in mice (Vaden et al 2019). Thus these large pools suggest reliable synaptic transmission even at high-frequency stimulation; hence a rapid depletion of the RRP and RP could be prevented by replenishment of synaptic vesicles from a large resting pool.…”

Section: Fig 3: Innervation Pattern Of Synaptic Boutons In Differentmentioning

confidence: 98%

“…In addition, the size and time course of action potential evoked Ca 2+ influx Sakmann 1996, 1998;Bischofberger and Jonas 2002), the occupancy of the putative Ca 2+ sensor driving vesicle fusion (Bollmann et al 2000;Schneggenburger and Neher 2000), the equilibration of intracellular Ca 2+ with the endogenous Ca 2+ buffer, and the eventual Ca 2+ -clearance (Helmchen et al 1997) can be accurately measured. Furthermore, the latency, size and time course of evoked quantal and multiquantal EPSCs (Borst and Sakmann 1996;Silver et al 2003;Molnar et al 2016;Holderith et al 2016;Seeman et al 2018;Rollenhagen et al 2018;Vaden et al 2019; reviewed by Neher 2015; Chamberland and Toth 2016) can be determined. However, there are still steps in the signal cascades that at present can only be simulated (Yamada and Zucker 1992;Bertram et al 1999;Meinrenken et al 2002Meinrenken et al , 2003Freche et al 2011).…”

Section: Historical Backgroundmentioning

confidence: 99%

“…On the postsynaptic side, the time course and amplitude of spontaneous and evoked excitatory postsynaptic potentials (EPSCs) were used to infer the characteristics of quantal release (Henze et al 1997;Silver et al 2003;Biro et al 2005;Szabadics et al 2006;Saviane and Silver 2006;Rollenhagen et al 2018;Vaden et al 2019). This interference requires simulations of the transient increase of the glutamate concentration in the synaptic cleft, reversible binding of glutamate to appropriate glutamate receptors and eventual uptake and diffusion of glutamate out of the cleft (Freche et al 2011).…”

Section: Historical Backgroundmentioning

confidence: 99%

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Synapses: Multitasking Global Players in the Brain

Lübke¹,

Rollenhagen²

2019

Neuroforum

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AbstractSynapses are key elements in the communication between neurons in any given network of the normal adult, developmental and pathologically altered brain. Synapses are composed of nearly the same structural subelements: a presynaptic terminal containing mitochondria with an ultrastructurally visible density at the pre- and postsynaptic apposition zone. The presynaptic density is composed of a cocktail of various synaptic proteins involved in the binding, priming and docking of synaptic vesicles inducing synaptic transmission. Individual presynaptic terminals (synaptic boutons) contain a couple of hundred up to thousands of synaptic vesicles. The pre- and postsynaptic densities are separated by a synaptic cleft. The postsynaptic density, also containing various synaptic proteins and more importantly various neurotransmitter receptors and their subunits specifically composed and arranged at individual synaptic complexes, reside at the target structures of the presynaptic boutons that could be somata, dendrites, spines or initial segments of axons.Beside the importance of the network in which synapses are integrated, their individual structural composition critically determines the dynamic properties within a given connection or the computations of the entire network, in particular, the number, size and shape of the active zone, the structural equivalent to a functional neurotransmitter release site, together with the size and organization of the three functionally defined pools of synaptic vesicles, namely the readily releasable, the recycling and the resting pool, are important structural subelements governing the ‘behavior’ of synaptic complexes within a given network such as the cortical column.In the late last century, neuroscientists started to generate quantitative 3D-models of synaptic boutons and their target structures that is one possible way to correlate structure with function, thus allowing reliable predictions about their function. The re-introduction of electron microscopy (EM) as an important tool achieved by modern high-end, high-resolution transmission-EM, focused ion beam scanning-EM, CRYO-EM and EM-tomography have enormously improved our knowledge about the synaptic organization of the brain not only in various animal species, but also allowed new insights in the ‘microcosms’ of the human brain in health and disease.

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“…Indeed, at hMFBs, an increase in docked vesicles has been proposed as a mechanism for post-tetanic-potentiation (Vandael et al, 2020). At cerebellar parallel and climbing fiber synapses, PKA and its vesicle associated target, synapsin, dynamically control release site occupancy and dictate the number of vesicles released per action potential without altering P r (Vaden et al, 2019). Moreover, activation of silent synapses and/or addition of release sites have been suggested as potential mechanisms for the expression of presynaptic LTP at hMFBs (Tong et al, 1996;Emptage et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

Orlando

Dvorzhak

Bruentgens

et al. 2020

Preprint

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Synaptic plasticity is a cellular model for learning and memory. However, the expression mechanisms underlying presynaptic forms of plasticity are not well understood. Here, we investigate functional and structural correlates of long-term potentiation at large hippocampal mossy fiber boutons induced by the adenylyl cyclase activator forskolin. We performed two-photon imaging of the genetically encoded glutamate sensor iGlu u that revealed an increase in the surface area used for glutamate release at potentiated terminals. Moreover, time-gated stimulated emission depletion microscopy revealed no change in the coupling distance between immunofluorescence signals from calcium channels and release sites. Finally, by high-pressure freezing and transmission electron microscopy analysis, we found a fast remodeling of synaptic ultrastructure at potentiated boutons : synaptic vesicles dispersed in the terminal and accumulated at the active zones, while active zone density and synaptic complexity increased. We suggest that these rapid and early structural rearrangements likely enable long-term increase in synaptic strength.

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The readily-releasable pool dynamically regulates multivesicular release

Cited by 48 publications

References 94 publications

Area-specific synapse structure in branched axons reveals a subcellular level of complexity in thalamocortical networks

Area-specific synapse structure in branched axons reveals a subcellular level of complexity in thalamocortical networks

Synapses: Multitasking Global Players in the Brain

Increased and synchronous recruitment of release sites underlies hippocampal mossy fiber presynaptic potentiation

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