scholarly journals Rapid homeostatic modulation of transsynaptic nanocolumn rings

2021 ◽  
Author(s):  
Paola Muttathukunnel ◽  
Patrick Frei ◽  
Sarah Perry ◽  
Dion Dickman ◽  
Martin Mueller
Keyword(s):  
Glutamate Receptor ◽  
Neurotransmitter Release ◽  
Information Transfer ◽  
Stimulated Emission ◽  
Homeostatic Plasticity ◽  
Synaptic Efficacy ◽  
Molecular Architecture ◽  
Neural Information ◽  
Active Zones ◽  
Chemical Synapses

Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization, and how synaptic nano-architecture is transsynaptically regulated to achieve stable synaptic transmission remains enigmatic. Using time-gated stimulated emission depletion (gSTED) microscopy at the Drosophila neuromuscular junction, we here find that presynaptic nano-rings formed by the active-zone scaffold Bruchpilot (Brp) precisely align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor ~5 transsynaptically-aligned Brp-GluR nanocolumns. Intriguingly, acute GluR impairment rapidly triggers the formation of new transsynaptic nanocolumns on the minute time scale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic reorganization preceding presynaptic modulation. Finally, the auxiliary GluR subunit Neto-B; promotes structural and functional homeostatic plasticity. Thus, transsynaptic nanocolumns arrange in stereotypic rings that are rapidly modulated during homeostatic plasticity to stabilize synaptic efficacy.

scholarly journals Postsynaptic Neuroligin-1 Mediates Presynaptic Endocytosis During Neuronal Activity

2021 ◽  
Vol 14 ◽  
Author(s):  
Jiaqi Keith Luo ◽  
Holly Melland ◽  
Jess Nithianantharajah ◽  
Sarah L. Gordon
Keyword(s):  
Ampa Receptors ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
High Fidelity ◽  
Excitatory Synapses ◽  
Synaptic Efficacy ◽  
Molecular Architecture ◽  
Adhesion Protein ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Release

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

scholarly journals Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

2019 ◽  
Vol 218 (3) ◽  
pp. 993-1010 ◽  
Author(s):  
Lilian A. Patrón ◽  
Kei Nagatomo ◽  
David Tyler Eves ◽  
Mays Imad ◽  
Kimberly Young ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Motor Neurons ◽  
Ubiquitin Ligase ◽  
Neurotransmitter Release ◽  
Neuromuscular Junctions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Independent Functions ◽  
Synaptic Boutons

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

Bringing light to the inner life of synapses

e-Neuroforum ◽  
2011 ◽  
Vol 17 (4) ◽  
Author(s):  
S.J. Sigrist ◽  
C. Wichmann
Keyword(s):  
Information Transfer ◽  
Super Resolution ◽  
Suitable Model ◽  
Molecular Architecture ◽  
Inner Life ◽  
Apply Genetic ◽  
Communication Devices ◽  
Conventional Microscopy ◽  
Chemical Synapses ◽  
And Function

AbstractChemical synapses are pivotal for information transfer and storage within neuronal circuit­y. At the same time, various diseases of the nervous system most likely originate from disturbances in synapse structure and function. Synapses are very fast, extremely con­trolled and effective communication devices, with synaptic vesicles fusing at specialized membrane domains associated with highly-ordered protein architectures (cytomatrices) traditionally seen using electron microsco­py. Drosophila synapses with prominent cytomatrices called T-bars provide per se a highly suitable model system to apply genetic analysis to the roles of these protein architectures. Here we describe the principles behind these techniques as well as their application to the analysis of the molecular architecture of the synapse. In this context, the advent of super-resolution light microscopy methods yielding two- to 10-fold higher resolution than conventional microscopy has provided an efficient tool.

scholarly journals Endogenous tagging reveals differential regulation of Ca2+ channels at single AZs during presynaptic homeostatic potentiation and depression

2017 ◽  
Author(s):  
Scott J. Gratz ◽  
Pragya Goel ◽  
Joseph J. Bruckner ◽  
Roberto X. Hernandez ◽  
Karam Khateeb ◽  
...  
Keyword(s):  
Information Flow ◽  
Neurotransmitter Release ◽  
Synaptic Strength ◽  
Live Imaging ◽  
Differential Regulation ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Multiple Forms ◽  
Active Zones ◽  
Ca2 Channels

AbstractNeurons communicate through Ca2+-dependent neurotransmitter release at presynaptic active zones (AZs). Neurotransmitter release properties play a key role in defining information flow in circuits and are tuned during multiple forms of plasticity. Despite their central role in determining neurotransmitter release properties, little is known about how Ca2+ channel levels are modulated to calibrate synaptic function. We used CRISPR to tag the Drosophila CaV2 Ca2+ channel Cacophony (Cac) and investigated the regulation of endogenous Ca2+ channels during homeostatic plasticity in males in which all endogenous Cac channels are tagged. We found that heterogeneously distributed Cac is highly predictive of neurotransmitter release probability at individual AZs and differentially regulated during opposing forms of presynaptic homeostatic plasticity. Specifically, Cac levels at AZ are increased during chronic and acute presynaptic homeostatic potentiation (PHP), and live imaging during acute expression of PHP reveals proportional Ca2+ channel accumulation across heterogeneous AZs. In contrast, endogenous Cac levels do not change during presynaptic homeostatic depression (PHD), implying that the reported reduction in Ca2+ influx during PHD is achieved through functional adaptions to pre-existing Ca2+ channels. Thus, distinct mechanisms bi-directionally modulate presynaptic Ca2+ levels to maintain stable synaptic strength in response to diverse challenges, with Ca2+ channel abundance providing a rapidly tunable substrate for potentiating neurotransmitter release over both acute and chronic timescales.

scholarly journals Postsynaptic neuroligin-1 mediates presynaptic endocytosis during neuronal activity

2021 ◽  
Author(s):  
Jiaqi Keith Luo ◽  
Holly Melland ◽  
Jess Nithianantharajah ◽  
Sarah L Gordon
Keyword(s):  
Ampa Receptors ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
High Fidelity ◽  
Excitatory Synapses ◽  
Synaptic Efficacy ◽  
Molecular Architecture ◽  
Adhesion Protein ◽  
Presynaptic Nerve Terminal ◽  
Presynaptic Release

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn-1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

scholarly journals Rapid active zone remodeling consolidates presynaptic potentiation

2018 ◽  
Author(s):  
Mathias A. Böhme ◽  
Anthony W. McCarthy ◽  
Andreas T. Grasskamp ◽  
Christine B. Beuschel ◽  
Pragya Goel ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Release Site ◽  
Scaffold Proteins ◽  
Homeostatic Plasticity ◽  
Discrete Subset ◽  
Molecular Sequence ◽  
Central Neurons ◽  
Presynaptic Plasticity ◽  
Active Zones ◽  
Plastic Changes

AbstractSynaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain functionality during perturbations and enable memory formation. Postsynaptic plasticity targets neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist of nano-modular release site units and identify a molecular sequence adding more modules within minutes of plasticity induction. This requires cognate transport machinery and a discrete subset of AZ scaffold proteins. Structural remodeling is not required for the immediate potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the neuromuscular junction also impair shot-term memory when central neurons are targeted, suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic potentiation capitalizes on available material, it triggers the coincident incorporation of modular release sites to consolidate stable synapse function.

scholarly journals Nonlinear feedback drives homeostatic plasticity in H2O2 stress response

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Youlian Goulev ◽  
Sandrine Morlot ◽  
Audrey Matifas ◽  
Bo Huang ◽  
Mikael Molin ◽  
...  
Keyword(s):  
Live Cell Imaging ◽  
Regulatory Networks ◽  
Transcriptional Response ◽  
Genetic Regulatory Networks ◽  
Homeostatic Plasticity ◽  
Mild Stress ◽  
Molecular Architecture ◽  
Nonlinear Feedback ◽  
Hormetic Effect ◽  
Stress Patterns

Homeostatic systems that rely on genetic regulatory networks are intrinsically limited by the transcriptional response time, which may restrict a cell’s ability to adapt to unanticipated environmental challenges. To bypass this limitation, cells have evolved mechanisms whereby exposure to mild stress increases their resistance to subsequent threats. However, the mechanisms responsible for such adaptive homeostasis remain largely unknown. Here, we used live-cell imaging and microfluidics to investigate the adaptive response of budding yeast to temporally controlled H2O2 stress patterns. We demonstrate that acquisition of tolerance is a systems-level property resulting from nonlinearity of H2O2 scavenging by peroxiredoxins and our study reveals that this regulatory scheme induces a striking hormetic effect of extracellular H2O2 stress on replicative longevity. Our study thus provides a novel quantitative framework bridging the molecular architecture of a cellular homeostatic system to the emergence of nonintuitive adaptive properties.

scholarly journals The auxiliary glutamate receptor subunit dSol-1 promotes presynaptic neurotransmitter release and homeostatic potentiation

2020 ◽  
Vol 117 (41) ◽  
pp. 25830-25839
Author(s):  
Beril Kiragasi ◽  
Pragya Goel ◽  
Sarah Perry ◽  
Yifu Han ◽  
Xiling Li ◽  
...  
Keyword(s):  
Neurotransmitter Release ◽  
Homeostatic Regulation ◽  
Auxiliary Subunits ◽  
Auxiliary Subunit ◽  
Glutamate Receptor Subunit ◽  
Synaptic Functions ◽  
Cub Domain ◽  
Active Zones ◽  
Domain Protein ◽  
Dependent Mechanism

Presynaptic glutamate receptors (GluRs) modulate neurotransmitter release and are physiological targets for regulation during various forms of plasticity. Although much is known about the auxiliary subunits associated with postsynaptic GluRs, far less is understood about presynaptic auxiliary GluR subunits and their functions. At theDrosophilaneuromuscular junction, a presynaptic GluR,DKaiR1D, localizes near active zones and operates as an autoreceptor to tune baseline transmission and enhance presynaptic neurotransmitter release in response to diminished postsynaptic GluR functionality, a process referred to as presynaptic homeostatic potentiation (PHP). Here, we identify an auxiliary subunit that collaborates with DKaiR1D to promote these synaptic functions. This subunit, dSol-1, is the homolog of theCaenorhabditis elegansCUB (Complement C1r/C1s, Uegf, Bmp1) domain protein Sol-1. We find thatdSol-1functions in neurons to facilitate baseline neurotransmission and to enable PHP expression, properties shared withDKaiR1D. Intriguingly, presynaptic overexpression ofdSol-1is sufficient to enhance neurotransmitter release through aDKaiR1D-dependent mechanism. Furthermore,dSol-1is necessary to rapidly increase the abundance of DKaiR1D receptors near active zones during homeostatic signaling. Together with recent work showing the CUB domain protein Neto2 is necessary for the homeostatic modulation of postsynaptic GluRs in mammals, our data demonstrate that dSol-1 is required for the homeostatic regulation of presynaptic GluRs. Thus, we propose that CUB domain proteins are fundamental homeostatic modulators of GluRs on both sides of the synapse.

Neurotransmitter Release: Priming at Presynaptic Active Zones

2008 ◽  
pp. 2834-2839
Author(s):  
Hiroshi Kawabe ◽  
Frederique Varoqueaux ◽  
Nils Brose
Keyword(s):  
Neurotransmitter Release ◽  
Active Zones
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