scholarly journals Maintenance of homeostatic plasticity at the Drosophila neuromuscular synapse requires continuous IP3-directed signaling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Thomas D James ◽  
Danielle J Zwiefelhofer ◽  
C Andrew Frank
Keyword(s):  
Ryanodine Receptors ◽  
Neuromuscular Synapse ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Editorial Note ◽  
Ip3 Receptors ◽  
Two Phases ◽  
Larval Neuromuscular Junction ◽  
Retrograde Signal ◽  
Maintenance Process

Synapses and circuits rely on neuroplasticity to adjust output and meet physiological needs. Forms of homeostatic synaptic plasticity impart stability at synapses by countering destabilizing perturbations. The Drosophila melanogaster larval neuromuscular junction (NMJ) is a model synapse with robust expression of homeostatic plasticity. At the NMJ, a homeostatic system detects impaired postsynaptic sensitivity to neurotransmitter and activates a retrograde signal that restores synaptic function by adjusting neurotransmitter release. This process has been separated into temporally distinct phases, induction and maintenance. One prevailing hypothesis is that a shared mechanism governs both phases. Here, we show the two phases are separable. Combining genetics, pharmacology, and electrophysiology, we find that a signaling system consisting of PLCβ, inositol triphosphate (IP3), IP3 receptors, and Ryanodine receptors is required only for the maintenance of homeostatic plasticity. We also find that the NMJ is capable of inducing homeostatic signaling even when its sustained maintenance process is absent.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

scholarly journals Maintenance of homeostatic plasticity at the Drosophila neuromuscular synapse requires continuous IP3-directed signaling

2018 ◽  
Author(s):  
Thomas D. James ◽  
Danielle J. Zwiefelhofer ◽  
C. Andrew Frank
Keyword(s):  
Ryanodine Receptors ◽  
Neuromuscular Synapse ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Inositol Triphosphate ◽  
Homeostatic Synaptic Plasticity ◽  
Two Phases ◽  
Larval Neuromuscular Junction ◽  
Retrograde Signal ◽  
Maintenance Process

ABSTRACTSynapses and circuits rely on neuroplasticity to adjust output and meet physiological needs. Forms of homeostatic synaptic plasticity impart stability at synapses by countering destabilizing perturbations. The Drosophila melanogaster larval neuromuscular junction (NMJ) is a model synapse with robust expression of homeostatic plasticity. At the NMJ, a homeostatic system detects impaired postsynaptic sensitivity to neurotransmitter and activates a retrograde signal that restores synaptic function by adjusting neurotransmitter release. This process has been separated into temporally distinct phases, induction and maintenance. One prevailing hypothesis is that a shared mechanism governs both phases. Here we show the two phases are separable. Combining genetics, pharmacology, and electrophysiology, we find that a signaling system consisting of PLCβ, inositol triphosphate (IP3), IP3 receptors, and Ryanodine receptors is required only for the maintenance of homeostatic plasticity. We also find that the NMJ is capable of inducing homeostatic signaling even when its sustained maintenance process is absent.

scholarly journals Deregulation of Ca2+-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes

2021 ◽  
Vol 22 (10) ◽  
pp. 5109
Author(s):  
Egor A. Turovsky ◽  
Maria V. Turovskaya ◽  
Vladimir V. Dynnik
Keyword(s):  
Cell Size ◽  
Ryanodine Receptors ◽  
Fluorescent Microscopy ◽  
Rhythmic Activity ◽  
Ip3 Receptors ◽  
Signaling Systems ◽  
White Adipocytes ◽  
Inhibitory Analysis ◽  
Hormonal Resistance ◽  
The Impact

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca2+-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP3-receptors (PLC/IP3R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)–dependent Ca2+ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors’ interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca2+]i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP3R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5–15% vs. 30–80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca2+-signaling systems deregulation, and development of general hormonal resistance to obesity.

scholarly journals A novel synaptic plasticity rule explains homeostasis of neuromuscular transmission

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Gilles Ouanounou ◽  
Gérard Baux ◽  
Thierry Bal
Keyword(s):  
Muscle Cell ◽  
Neurotransmitter Release ◽  
Neuromuscular Transmission ◽  
Ex Vivo ◽  
Neuromuscular Synapse ◽  
Skeletal Muscle Cell ◽  
Synaptic Potentiation ◽  
Cell Excitability ◽  
Nerve Muscle ◽  
Retrograde Signal

Excitability differs among muscle fibers and undergoes continuous changes during development and growth, yet the neuromuscular synapse maintains a remarkable fidelity of execution. Here we show in two evolutionarily distant vertebrates (Xenopus laevis cell culture and mouse nerve-muscle ex-vivo) that the skeletal muscle cell constantly senses, through two identified calcium signals, synaptic events and their efficacy in eliciting spikes. These sensors trigger retrograde signal(s) that control presynaptic neurotransmitter release, resulting in synaptic potentiation or depression. In the absence of spikes, synaptic events trigger potentiation. Once the synapse is sufficiently strong to initiate spiking, the occurrence of these spikes activates a negative retrograde feedback. These opposing signals dynamically balance the synapse in order to continuously adjust neurotransmitter release to a level matching current muscle cell excitability.

scholarly journals Neuronal and synaptic plasticity in the visual thalamus in mouse models of glaucoma

2020 ◽  
Author(s):  
Matthew J. Van Hook ◽  
Corrine Monaco ◽  
Jennie C. Smith
Keyword(s):  
Mouse Models ◽  
Ganglion Cells ◽  
Brain Regions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Intrinsic Excitability ◽  
Dependent Manner ◽  
Functional Changes ◽  
Genetic Mouse Model

AbstractHomeostatic plasticity plays important roles in regulating synaptic and intrinsic neuronal function to stabilize output following perturbations to circuit activity. In glaucoma, a neurodegenerative disease of the visual system commonly associated with elevated intraocular pressure (IOP), early disease is associated with altered synaptic inputs to retinal ganglion cells (RGCs), changes in RGC intrinsic excitability, and deficits in optic nerve transport and energy metabolism. These early functional changes can precede RGC degeneration and are likely to alter RGC outputs to their target structures in the brain and thereby trigger homeostatic changes in synaptic and neuronal properties in those brain regions. In this study, we sought to determine whether and how neuronal and synaptic function is altered in the dorsal lateral geniculate nucleus (dLGN), an important RGC projection target in the thalamus, and how functional changes relate to IOP. We accomplished this using patch-clamp recordings from thalamocortical (TC) relay neurons in the dLGN in two established mouse models of glaucoma – the DBA/2J (D2) genetic mouse model and an inducible glaucoma model with intracameral microbead injections to elevate IOP. We found that the intrinsic excitability of TC neurons was enhanced in D2 mice and these functional changes were mirrored in recordings of TC neurons from microbead-injected mice. Notably, many neuronal properties were correlated with IOP in older D2 mice, but not younger D2 mice or microbead-injected mice. The frequency of miniature excitatory synaptic currents (mEPSCs) was reduced in both ages of D2 mice, and vGlut2 staining of RGC synaptic terminals was reduced in an IOP-dependent manner in older D2 mice. Among D2 mice, functional changes observed in younger mice without elevated IOP were distinct from those observed in older mice with elevated IOP and RGC degeneration, suggesting that glaucoma-associated changes to neurons in the dLGN might represent a combination of stabilizing/homeostatic plasticity at earlier stages and pathological dysfunction at later stages.

scholarly journals The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Viviana Pérez ◽  
Francisca Bermedo-Garcia ◽  
Diego Zelada ◽  
Felipe A. Court ◽  
Miguel Ángel Pérez ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuronal Damage ◽  
Neuromuscular Synapse ◽  
Force Production ◽  
Synaptic Function ◽  
Neurotrophin Receptor ◽  
Acetylcholinesterase Inhibition ◽  
Pharmacological Intervention

Abstract The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

scholarly journals The EHD protein Past1 controls postsynaptic membrane elaboration and synaptic function

2015 ◽  
Vol 26 (18) ◽  
pp. 3275-3288 ◽  
Author(s):  
Kate Koles ◽  
Emily M. Messelaar ◽  
Zachary Feiger ◽  
Crystal J. Yu ◽  
C. Andrew Frank ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Postsynaptic Membrane ◽  
Lipid Binding ◽  
Synaptic Function ◽  
Muscle Membrane ◽  
Membrane Remodeling ◽  
Cellular Functions ◽  
Synaptic Homeostasis ◽  
Larval Neuromuscular Junction ◽  
Lipid Binding Proteins

Membranes form elaborate structures that are highly tailored to their specialized cellular functions, yet the mechanisms by which these structures are shaped remain poorly understood. Here, we show that the conserved membrane-remodeling C-terminal Eps15 Homology Domain (EHD) protein Past1 is required for the normal assembly of the subsynaptic muscle membrane reticulum (SSR) at the Drosophila melanogaster larval neuromuscular junction (NMJ). past1 mutants exhibit altered NMJ morphology, decreased synaptic transmission, reduced glutamate receptor levels, and a deficit in synaptic homeostasis. The membrane-remodeling proteins Amphiphysin and Syndapin colocalize with Past1 in distinct SSR subdomains and collapse into Amphiphysin-dependent membrane nodules in the SSR of past1 mutants. Our results suggest a mechanism by which the coordinated actions of multiple lipid-binding proteins lead to the elaboration of increasing layers of the SSR and uncover new roles for an EHD protein at synapses.

scholarly journals Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals

2017 ◽  
Vol 114 (29) ◽  
pp. 7525-7530 ◽  
Author(s):  
Anna V. Maltsev ◽  
Victor A. Maltsev ◽  
Michael D. Stern
Keyword(s):  
Phase Transition ◽  
Statistical Physics ◽  
Calcium Release ◽  
Cell Function ◽  
Particle System ◽  
Signal To Noise Ratio ◽  
Ryanodine Receptors ◽  
High Amplitude ◽  
Ip3 Receptors ◽  
Cooperative Action

Intracellular Ca signals represent a universal mechanism of cell function. Messages carried by Ca are local, rapid, and powerful enough to be delivered over the thermal noise. A higher signal-to-noise ratio is achieved by a cooperative action of Ca release channels such as IP3 receptors or ryanodine receptors arranged in clusters (release units) containing a few to several hundred release channels. The channels synchronize their openings via Ca-induced Ca release, generating high-amplitude local Ca signals known as puffs in neurons and sparks in muscle cells. Despite the positive feedback nature of the activation, Ca signals are strictly confined in time and space by an unexplained termination mechanism. Here we show that the collective transition of release channels from an open to a closed state is identical to the phase transition associated with the reversal of magnetic field in an Ising ferromagnet. Our simple quantitative criterion closely predicts the Ca store depletion level required for spark termination for each cluster size. We further formulate exact requirements that a cluster of release channels should satisfy in any cell type for our mapping to the Ising model and the associated formula to remain valid. Thus, we describe deterministically the behavior of a system on a coarser scale (release unit) that is random on a finer scale (release channels), bridging the gap between scales. Our results provide exact mapping of a nanoscale biological signaling model to an interacting particle system in statistical physics, making the extensive mathematical apparatus available to quantitative biology.

scholarly journals Selective visual processing across competition episodes: a theory of task-driven visual attention and working memory

2013 ◽  
Vol 368 (1628) ◽  
pp. 20130060 ◽  
Author(s):  
Werner X. Schneider
Keyword(s):  
Working Memory ◽  
Visual Attention ◽  
Visual Processing ◽  
Attentional Resource ◽  
Short Term ◽  
Phase 3 ◽  
Search Processes ◽  
Current Task ◽  
Two Phases ◽  
Maintenance Process

The goal of this review is to introduce a theory of task-driven visual attention and working memory (TRAM). Based on a specific biased competition model, the ‘theory of visual attention’ (TVA) and its neural interpretation (NTVA), TRAM introduces the following assumption. First, selective visual processing over time is structured in competition episodes. Within an episode, that is, during its first two phases, a limited number of proto-objects are competitively encoded—modulated by the current task—in activation-based visual working memory (VWM). In processing phase 3, relevant VWM objects are transferred via a short-term consolidation into passive VWM. Second, each time attentional priorities change (e.g. after an eye movement), a new competition episode is initiated. Third, if a phase 3 VWM process (e.g. short-term consolidation) is not finished, whereas a new episode is called, a protective maintenance process allows its completion. After a VWM object change, its protective maintenance process is followed by an encapsulation of the VWM object causing attentional resource costs in trailing competition episodes. Viewed from this perspective, a new explanation of key findings of the attentional blink will be offered. Finally, a new suggestion will be made as to how VWM items might interact with visual search processes.

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