scholarly journals Impaired EAT-4 Vesicular Glutamate Transporter Leads to Defective Nocifensive Response of Caenorhabditis elegans to Noxious Heat

2019 ◽  
Author(s):  
Sophie Leonelli ◽  
Bruno Nkambeu ◽  
Francis Beaudry
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Transporter ◽  
Mechanical Stimuli ◽  
Pain Sensation ◽  
Noxious Heat ◽  
Excitatory Neurotransmitter ◽  
Glutamate Signaling ◽  
C Elegans ◽  
Avoidance Behaviors ◽  
Neurotransmitter Glutamate

AbstractIn mammals, glutamate is an important excitatory neurotransmitter. Glutamate and glutamate receptors are found in areas specifically involved in pain sensation, transmission and transduction such as peripheral nervous system, spinal cord and brain. In C. elegans, several studies have suggested glutamate pathways are associated with withdrawal responses to mechanical stimuli and to chemical repellents. However, few evidences demonstrate that glutamate pathways are important to mediate nocifensive response to noxious heat. The thermal avoidance behavior of C. elegans was studied and results illustrated that mutants of glutamate receptors (glr-1, glr-2, nmr-1, nmr-2) behaviors was not affected. However, results revealed that all strains of eat-4 mutants, C. elegans vesicular glutamate transporters, displayed defective thermal avoidance behaviors. Due to the interplay between the glutamate and the FLP-18/FLP-21/NPR-1 pathways, we analyzed the effectors FLP-18 and FLP-21 at the protein level, we did not observebiologically significant differences compared to N2 (WT) strain (fold-change < 2) except for the IK602 strain. The data presented in this manuscript reveals that glutamate signaling pathways are essential to elicit a nocifensive response to noxious heat in C. elegans.

Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit

2021 ◽  
Author(s):  
Jung-Hwan Choi ◽  
Lauren Bayer Horowitz ◽  
Niels Ringstad
Keyword(s):  
Synaptic Vesicles ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Synaptic Function ◽  
Functional Coupling ◽  
Glutamate Signaling ◽  
C Elegans ◽  
Vesicular Transporters ◽  
Chemical Synapses

At chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.

scholarly journals Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jung-Hwan Choi ◽  
Lauren Bayer Horowitz ◽  
Niels Ringstad
Keyword(s):  
Synaptic Vesicles ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Synaptic Function ◽  
Functional Coupling ◽  
Glutamate Signaling ◽  
C Elegans ◽  
Vesicular Transporters ◽  
Chemical Synapses

AbstractAt chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.

Interaction between glutamate signalling and immune attack in damaging oligodendrocytes

2007 ◽  
Vol 3 (4) ◽  
pp. 281-285 ◽  
Author(s):  
Carlos Matute
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Uptake ◽  
Kainate Receptors ◽  
Glutamate Excitotoxicity ◽  
Excitatory Neurotransmitter ◽  
Glutamate Signaling ◽  
Immune Attack ◽  
Glutamate Homeostasis

AbstractGlutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca2+ overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca2+ overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.

scholarly journals Aminooxadiazolyl kainic acid reveals that kainic acid receptors contribute to astrocytoma glutamate signaling

2021 ◽  
Author(s):  
Mitra Sadat Tabatabaee ◽  
Zhenlin Tian ◽  
Julien Gibon ◽  
Frederic Menard
Keyword(s):  
Nervous System ◽  
Natural Product ◽  
Kainic Acid ◽  
Rational Design ◽  
Calcium Influx ◽  
Excitatory Neurotransmitter ◽  
Glutamate Signaling ◽  
Neurotransmitter Glutamate ◽  
In Cells

ABSTRACTThe excitatory neurotransmitter glutamate triggers a Ca2+ rise and the extension of processes in astrocytes. Our results suggest that kainic acid receptors (KAR) can independently initiate glutamate signaling in astrocytoma U118-MG cells. The natural product kainic acid triggered glioexcitablity in cells and was inhibited by the KAR antagonist CNQX, but its activity was lower than glutamate on KARs. We created a new heteroaryl kainoid based on rational design: aminooxadiazolyl kainic acid 1 (AODKA). AODKA induced a larger calcium influx and a faster processes extension than kainic acid in U118-MG cells. AODKA is a new tool to study KAR activity in the nervous system.Abstract Figure

scholarly journals Distribution of Vesicular Glutamate Transporter-2 Messenger Ribonucleic Acid and Protein in the Septum-Hypothalamus of the Rat

Endocrinology ◽  
2003 ◽  
Vol 144 (2) ◽  
pp. 662-670 ◽  
Author(s):  
Winston Lin ◽  
Kyle McKinney ◽  
Liansheng Liu ◽  
Shruti Lakhlani ◽  
Lothar Jennes
Keyword(s):  
Glutamate Transporter ◽  
Brain Regions ◽  
Female Rats ◽  
Vesicular Glutamate Transporter ◽  
Excitatory Neurotransmitter ◽  
Adrenal Steroid ◽  
Messenger Ribonucleic Acid ◽  
Glutamatergic Neurons ◽  
Neurotransmitter Glutamate ◽  
Arcuate Nuclei

The excitatory neurotransmitter glutamate is involved in the control of most, perhaps all, neuroendocrine systems, yet the sites of glutamatergic neurons and their processes are unknown. Here, we used in situ hybridization and immunohistochemistry for the neuron-specific vesicular glutamate transporter-2 (VGLUT2) to identify the neurons in female rats that synthesize the neurotransmitter glutamate as well as their projections throughout the septum-hypothalamus. The results show that glutamatergic neurons are present in the septum-diagonal band complex and throughout the hypothalamus. The preoptic area and ventromedial and dorsomedial nuclei are particularly rich in glutamatergic neurons, followed by the supraoptic, paraventricular, and arcuate nuclei, whereas the suprachiasmatic nucleus does not express detectable amounts of VGLUT2 mRNA. Immunoreactive neurites are seen in very high densities in all regions analyzed, particularly in the preoptic region, followed by the ventromedial, dorsomedial, and arcuate nuclei as well as the external layer of the median eminence, whereas the mammillary complex does not exhibit VGLUT2 immunoreactivity. Many VGLUT2 immunoreactive fibers also contained synaptophysin, suggesting that the transporter is indeed localized to presynaptic terminals. Together, the results identify glutamatergic cell bodies throughout the septum-hypothalamus in region-specific patterns and show that glutamatergic nerve terminals are present in very large numbers such that most neurons in these brain regions can receive glutamatergic input. We examined the GnRH system as an example of a typical neuroendocrine system and could show that the GnRH perikarya are closely apposed by many VGLUT2-immunoreactive boutons, some of which also contained synaptophysin. The presence of VGLUT2 mRNA-containing cells in specific nuclei of the hypothalamus indicates that many neuroendocrine neurons coexpress glutamate as neurotransmitter, in addition to neuropeptides. These systems include the oxytocin, vasopressin, or CRH neurons as well as many others in the periventricular and mediobasal hypothalamus. The presence of VGLUT2 mRNA in steroid-sensitive regions of the hypothalamus, such as the anteroventral periventricular, paraventricular, or ventromedial nuclei indicates that gonadal and adrenal steroid can directly alter the functions of these glutamatergic neurons.

scholarly journals L-type Voltage-gated Calcium Channel Modulators Inhibit Glutamate-induced Morphology in Astrocytoma Cells

2019 ◽  
Author(s):  
Mitra Sadat Tabatabaee ◽  
Frederic Menard
Keyword(s):  
Confocal Imaging ◽  
Excitatory Neurotransmitter ◽  
Voltage Gated ◽  
Natural Properties ◽  
Glutamate Signaling ◽  
Astrocytoma Cells ◽  
Auxiliary Subunit ◽  
Voltage Gated Calcium Channels ◽  
Neurotransmitter Glutamate

ABSTRACTThe excitatory neurotransmitter glutamate evokes physiological responses within the astrocytic network that lead to fine morphological dynamics. However, the mechanism by which astrocytes couple glutamate sensing with cellular calcium rise remains unclear. Employing natural properties of U118-MG astrocytoma cells, we tested a possible connection between L-type voltage-gated calcium channels (Cav) and glutamate receptors. Using live confocal imaging and pharmacological inhibitors, the extension of U118-MG processes upon glutamate exposure are shown to depend mainly on extracellular calcium entry via L-type Cav’s. Inhibitors of the Cav α1 protein, decreased astrocytic filopodia extension; while, gabapentinoids, ligands of the Cav’s α2δ auxiliary subunit blocked all process growth. This study suggests that α2δ is the main contributor to Cav’s role in glutamate-dependent filopodiagenesis. It opens new avenues of research on the role of α2δ in neuron-astrocyte glutamate signaling and neurochemical signaling at tripartite synapses.

scholarly journals Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5

2018 ◽  
Author(s):  
Menachem Katz ◽  
Francis Corson ◽  
Wolfgang Keil ◽  
Anupriya Singhal ◽  
Andrea Bae ◽  
...  
Keyword(s):  
Animal Behavior ◽  
Glutamate Release ◽  
Repetitive Behavior ◽  
Glutamate Transporter ◽  
Repetitive Behaviors ◽  
Common Mechanism ◽  
Excitatory Neurotransmitter ◽  
C Elegans ◽  
Synaptic Release ◽  
Glial Glutamate Transporter

Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gαq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.

scholarly journals Liposomal Encapsulated FSC231, a PICK1 Inhibitor, Prevents the Ischemia/Reperfusion-Induced Degradation of GluA2-Containing AMPA Receptors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 636
Author(s):  
Lindsay M. Achzet ◽  
Fanny Astruc-Diaz ◽  
Phillip H. Beske ◽  
Nicholas R. Natale ◽  
Travis T. Denton ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Ampa Receptors ◽  
Research Effort ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
The United States ◽  
Excitatory Neurotransmitter ◽  
Protein Levels ◽  
Neurotransmitter Glutamate ◽  
Subsequent Degradation

Strokes remain one of the leading causes of disability within the United States. Despite an enormous amount of research effort within the scientific community, very few therapeutics are available for stroke patients. Cytotoxic accumulation of intracellular calcium is a well-studied phenomenon that occurs following ischemic stroke. This intracellular calcium overload results from excessive release of the excitatory neurotransmitter glutamate, a process known as excitotoxicity. Calcium-permeable AMPA receptors (AMPARs), lacking the GluA2 subunit, contribute to calcium cytotoxicity and subsequent neuronal death. The internalization and subsequent degradation of GluA2 AMPAR subunits following oxygen–glucose deprivation/reperfusion (OGD/R) is, at least in part, mediated by protein-interacting with C kinase-1 (PICK1). The purpose of the present study is to evaluate whether treatment with a PICK1 inhibitor, FSC231, prevents the OGD/R-induced degradation of the GluA2 AMPAR subunit. Utilizing an acute rodent hippocampal slice model system, we determined that pretreatment with FSC231 prevented the OGD/R-induced association of PICK1–GluA2. FSC231 treatment during OGD/R rescues total GluA2 AMPAR subunit protein levels. This suggests that the interaction between GluA2 and PICK1 serves as an important step in the ischemic/reperfusion-induced reduction in total GluA2 levels.

scholarly journals Pan-neuronal screening in Caenorhabditis elegans reveals asymmetric dynamics of AWC neurons is critical for thermal avoidance behavior

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ippei Kotera ◽  
Nhat Anh Tran ◽  
Donald Fu ◽  
Jimmy HJ Kim ◽  
Jarlath Byrne Rodgers ◽  
...  
Keyword(s):  
Avoidance Behavior ◽  
Calcium Imaging ◽  
Functional Screening ◽  
Noxious Heat ◽  
Thermal Nociception ◽  
C Elegans ◽  
Low Efficiency ◽  
Behavioral Transition ◽  
Thermal Stimuli

Understanding neural functions inevitably involves arguments traversing multiple levels of hierarchy in biological systems. However, finding new components or mechanisms of such systems is extremely time-consuming due to the low efficiency of currently available functional screening techniques. To overcome such obstacles, we utilize pan-neuronal calcium imaging to broadly screen the activity of the C. elegans nervous system in response to thermal stimuli. A single pass of the screening procedure can identify much of the previously reported thermosensory circuitry as well as identify several unreported thermosensory neurons. Among the newly discovered neural functions, we investigated in detail the role of the AWCOFF neuron in thermal nociception. Combining functional calcium imaging and behavioral assays, we show that AWCOFF is essential for avoidance behavior following noxious heat stimulation by modifying the forward-to-reversal behavioral transition rate. We also show that the AWCOFF signals adapt to repeated noxious thermal stimuli and quantify the corresponding behavioral adaptation.

scholarly journals Progressive recruitment of distal MEC-4 channels determines touch response strength in C. elegans

2019 ◽  
Author(s):  
S. Katta ◽  
A. Sanzeni ◽  
A. Das ◽  
M. Vergassola ◽  
M.B. Goodman
Keyword(s):  
Temporal Dynamics ◽  
Mechanical Strain ◽  
Tissue Mechanics ◽  
Mechanical Stimuli ◽  
Patch Clamp Recording ◽  
Open Probability ◽  
C Elegans ◽  
Somatosensory Neurons ◽  
Touch Response

AbstractTouch deforms, or strains, the skin beyond the immediate point of contact. The spatiotemporal nature of the touch-induced strain fields depend on the mechanical properties of the skin and the tissues below. Somatosensory neurons that sense touch branch out within the skin and rely on a set of mechano-electrical transduction channels distributed within their dendrites to detect mechanical stimuli. Here, we sought to understand how tissue mechanics shape touch-induced mechanical strain across the skin over time and how individual channels located in different regions of the strain field contribute to the overall touch response. We leveraged C. elegans’ touch receptor neurons (TRNs) as a simple model amenable to in vivo whole-cell patch clamp recording and an integrated experimental-computational approach to dissect the mechanisms underlying the spatial and temporal dynamics that we observed. Consistent with the idea that strain is produced at a distance, we show that delivering strong stimuli outside the anatomical extent of the neuron is sufficient to evoke MRCs. The amplitude and kinetics of the MRCs depended on both stimulus displacement and speed. Finally, we found that the main factor responsible for touch sensitivity is the recruitment of progressively more distant channels by stronger stimuli, rather than modulation of channel open probability. This principle may generalize to somatosensory neurons with more complex morphologies.SummaryThrough experiment and simulation, Katta et al. reveal that pushing faster and deeper recruits more and more distant mechano-electrical transduction channels during touch. The net result is a dynamic receptive field whose size and shape depends on tissue mechanics, stimulus parameters, and channel distribution within sensory neurons.

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