scholarly journals Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Xiling Li ◽  
Pragya Goel ◽  
Catherine Chen ◽  
Varun Angajala ◽  
Xun Chen ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Neurotransmitter Release ◽  
Genetic Manipulation ◽  
Receptor Expression ◽  
Homeostatic Plasticity ◽  
Postsynaptic Receptor ◽  
Vesicle Pools ◽  
Synaptic Structures

Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments.

scholarly journals Homeostatic synaptic depression is achieved through a regulated decrease in presynaptic calcium channel abundance

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Michael A Gaviño ◽  
Kevin J Ford ◽  
Santiago Archila ◽  
Graeme W Davis
Keyword(s):  
Synaptic Plasticity ◽  
Neuromuscular Junction ◽  
Action Potential ◽  
Calcium Channel ◽  
Neurotransmitter Release ◽  
Calcium Influx ◽  
Homeostatic Synaptic Plasticity ◽  
Action Potential Waveform ◽  
Presynaptic Calcium ◽  
Potential Waveform

Homeostatic signaling stabilizes synaptic transmission at the neuromuscular junction (NMJ) of Drosophila, mice, and human. It is believed that homeostatic signaling at the NMJ is bi-directional and considerable progress has been made identifying mechanisms underlying the homeostatic potentiation of neurotransmitter release. However, very little is understood mechanistically about the opposing process, homeostatic depression, and how bi-directional plasticity is achieved. Here, we show that homeostatic potentiation and depression can be simultaneously induced, demonstrating true bi-directional plasticity. Next, we show that mutations that block homeostatic potentiation do not alter homeostatic depression, demonstrating that these are genetically separable processes. Finally, we show that homeostatic depression is achieved by decreased presynaptic calcium channel abundance and calcium influx, changes that are independent of the presynaptic action potential waveform. Thus, we identify a novel mechanism of homeostatic synaptic plasticity and propose a model that can account for the observed bi-directional, homeostatic control of presynaptic neurotransmitter release.

Synaptotagmins: Beyond Presynaptic Neurotransmitter Release

2019 ◽  
Vol 26 (1) ◽  
pp. 9-15 ◽  
Author(s):  
Xuanang Wu ◽  
Shaoqin Hu ◽  
Xinjiang Kang ◽  
Changhe Wang
Keyword(s):  
Synaptic Plasticity ◽  
Neurotransmitter Release ◽  
Long Term Potentiation ◽  
Receptor Internalization ◽  
Long Term Depression ◽  
Receptor Endocytosis ◽  
Postsynaptic Receptor ◽  
Term Potentiation ◽  
Tightly Coupled

Synaptotagmins (Syts) are well-established primary Ca2+ sensors to initiate presynaptic neurotransmitter release. They also play critical roles in the docking, priming, and fusion steps of exocytosis, as well as the tightly coupled exo-endocytosis, in presynapses. A recent study by Awasthi and others (2019) shows that Syt3 Ca2+-dependently modulates the postsynaptic receptor endocytosis and thereby promotes the long-term depression (LTD) and the decay of long-term potentiation (LTP). This work highlights the importance of Syt3 in modulating long-term synaptic plasticity and, importantly, extends the function of Syt proteins from presynaptic neurotransmitter release to a new promising postsynaptic receptor internalization.

scholarly journals Calcium dependence of neurotransmitter release at a high fidelity synapse

2021 ◽  
Author(s):  
Abdelmoneim Eshra ◽  
Hartmut Schmidt ◽  
Jens Eilers ◽  
Stefan Hallermann
Keyword(s):  
Synaptic Plasticity ◽  
Release Rate ◽  
High Frequency ◽  
Neurotransmitter Release ◽  
Synaptic Vesicles ◽  
Mossy Fiber ◽  
High Fidelity ◽  
Fundamental Parameters ◽  
High Affinity ◽  
Vesicle Pools

The Ca2+-dependence of the recruitment, priming, and fusion of synaptic vesicles are fundamental parameters controlling neurotransmitter release and synaptic plasticity. Despite intense efforts, these important steps in the synaptic vesicles cycle remain poorly understood because disentangling recruitment, priming, and fusion of vesicles is technically challenging. Here, we investigated the Ca2+-sensitivity of these steps at cerebellar mossy fiber synapses, which are characterized by fast vesicle recruitment mediating high-frequency signaling. We found that the basal free Ca2+ concentration (<200 nM) critically controls action potential-evoked release, indicating a high-affinity Ca2+ sensor for vesicle priming. Ca2+ uncaging experiments revealed a surprisingly shallow and non-saturating relationship between release rate and intracellular Ca2+ concentration up to 50 μM. Sustained vesicle recruitment was Ca2+-independent. Finally, quantitative mechanistic release schemes with five Ca2+ binding steps incorporating rapid vesicle recruitment via parallel or sequential vesicle pools could explain our data. We thus show that co-existing high and low-affinity Ca2+ sensors mediate recruitment, priming, and fusion of synaptic vesicles at a high-fidelity synapse.

scholarly journals Bioengineered model of the human motor unit with physiologically functional neuromuscular junctions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rowan P. Rimington ◽  
Jacob W. Fleming ◽  
Andrew J. Capel ◽  
Patrick C. Wheeler ◽  
Mark P. Lewis
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Unit ◽  
Motor Nerve ◽  
Motor Units ◽  
Extracellular Matrices ◽  
Synaptic Membrane ◽  
Type I ◽  
Dependent Manner ◽  
Human Motor

AbstractInvestigations of the human neuromuscular junction (NMJ) have predominately utilised experimental animals, model organisms, or monolayer cell cultures that fail to represent the physiological complexity of the synapse. Consequently, there remains a paucity of data regarding the development of the human NMJ and a lack of systems that enable investigation of the motor unit. This work addresses this need, providing the methodologies to bioengineer 3D models of the human motor unit. Spheroid culture of iPSC derived motor neuron progenitors augmented the transcription of OLIG2, ISLET1 and SMI32 motor neuron mRNAs ~ 400, ~ 150 and ~ 200-fold respectively compared to monolayer equivalents. Axon projections of adhered spheroids exceeded 1000 μm in monolayer, with transcription of SMI32 and VACHT mRNAs further enhanced by addition to 3D extracellular matrices in a type I collagen concentration dependent manner. Bioengineered skeletal muscles produced functional tetanic and twitch profiles, demonstrated increased acetylcholine receptor (AChR) clustering and transcription of MUSK and LRP4 mRNAs, indicating enhanced organisation of the post-synaptic membrane. The number of motor neuron spheroids, or motor pool, required to functionally innervate 3D muscle tissues was then determined, generating functional human NMJs that evidence pre- and post-synaptic membrane and motor nerve axon co-localisation. Spontaneous firing was significantly elevated in 3D motor units, confirmed to be driven by the motor nerve via antagonistic inhibition of the AChR. Functional analysis outlined decreased time to peak twitch and half relaxation times, indicating enhanced physiology of excitation contraction coupling in innervated motor units. Our findings provide the methods to maximise the maturity of both iPSC motor neurons and primary human skeletal muscle, utilising cell type specific extracellular matrices and developmental timelines to bioengineer the human motor unit for the study of neuromuscular junction physiology.

scholarly journals Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS

2012 ◽  
Vol 7 (1) ◽  
pp. 10 ◽  
Author(s):  
Ruohan Xia ◽  
Yajuan Liu ◽  
Liuqing Yang ◽  
Jozsef Gal ◽  
Haining Zhu ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Drosophila Model ◽  
Neuron Apoptosis

scholarly journals Lola regulates glutamate receptor expression at the Drosophila neuromuscular junction

Biology Open ◽  
2012 ◽  
Vol 1 (4) ◽  
pp. 362-375 ◽  
Author(s):  
A. Fukui ◽  
M. Inaki ◽  
G. Tonoe ◽  
H. Hamatani ◽  
M. Homma ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Glutamate Receptor ◽  
Receptor Expression

scholarly journals A three-dimensional culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction and disease modeling

2018 ◽  
Author(s):  
Mohsen Afshar Bakooshli ◽  
Ethan S Lippmann ◽  
Ben Mulcahy ◽  
Nisha R Iyer ◽  
Christine T Nguyen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Human Skeletal Muscle ◽  
Disease Modeling ◽  
De Novo ◽  
Muscle Fibers ◽  
Three Dimensional ◽  
Adult Human

SummaryTwo-dimensional (2D) human skeletal muscle fiber cultures are ill equipped to support the contractile properties of maturing muscle fibers. This limits their application to the study of adult human neuromuscular junction (NMJ) development, a process requiring maturation of muscle fibers in the presence of motor neuron endplates. Here we describe a three-dimensional (3D) co-culture method whereby human muscle progenitors mixed with human pluripotent stem cell-derived motor neurons self-organize to form functional NMJ connections within two weeks. Functional connectivity between motor neuron endplates and muscle fibers is confirmed with calcium transient imaging and electrophysiological recordings. Notably, we only observed epsilon acetylcholine receptor subunit protein upregulation and activity in 3D co-culture. This demonstrates that the 3D co-culture system supports a developmental shift from the embryonic to adult form of the receptor that does not occur in 2D co-culture. Further, 3D co-culture treatments with myasthenia gravis patient sera shows the ease of studying human disease with the system. This work delivers a simple, reproducible, and adaptable method to model and evaluate adult human NMJ de novo development and disease in culture.

scholarly journals A genetic manipulation of motor neuron excitability does not alter locomotor output in Drosophila larvae

2014 ◽  
Author(s):  
Erin C. McKiernan
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Motor Behavior ◽  
Genetic Manipulation ◽  
Motor Output ◽  
Membrane Properties ◽  
Neuron Excitability ◽  
Motor Neuron Excitability ◽  
The Face

Motor activity, like that producing locomotion, is generated by networks of neurons. At the last output level of these networks are the motor neurons, which send signals to the muscles, causing them to contract. Current research in motor control is focused on finding out how motor neurons contribute to shaping the timing of motor behaviors. Are motor neurons just passive relayers of the signals they receive? Or, do motor neurons shape the signals before passing them on to the muscles, thereby influencing the timing of the behavior? It is now well accepted that motor neurons have active, intrinsic membrane properties - there are ion channels in the cell membrane that allow motor neurons to respond to input in non-linear and diverse ways. However, few direct tests of the role of motor neuron intrinsic properties in shaping motor behavior have been carried out, and many questions remain about the role of specific ion channel genes in motor neuron function. In this study, two potassium channel transgenes were expressed in Drosophila larvae, causing motor neurons to fire at lower levels of current stimulation and at higher frequencies, thereby increasing excitability. Mosaic animals were created in which some identified motor neurons expressed the transgenes while others did not. Motor output underlying crawling was compared in muscles innervated by control and experimental neurons in the same animals. Counterintuitively, no effect of the transgenic manipulation on motor output was seen. Future experiments are outlined to determine how the larval nervous system produces normal motor output in the face of altered motor neuron excitability.

Weakness

2018 ◽  
pp. 207-238
Author(s):  
Andrea C. Adams
Keyword(s):  
Nervous System ◽  
Neuromuscular Junction ◽  
Motor Neuron ◽  
Motor System ◽  
Lower Motor Neuron ◽  
Diagnostic Challenge ◽  
Common Complaint ◽  
Motor Nerves

Weakness is a common complaint. Most patients use the term weakness to imply fatigue, general illness, or myalgias. Determining whether a patient has actual neuromuscular weakness can be a diagnostic challenge. Disease of the motor system can occur at all levels of the nervous system. This chapter considers disorders of the lower motor neuron, including disorders of muscle (myopathies), the neuromuscular junction, and motor nerves.

Sign in / Sign up

Export Citation Format

Share Document