scholarly journals Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses

2020 ◽  
Vol 117 (25) ◽  
pp. 14503-14511 ◽  
Author(s):  
Julia Goncalves ◽  
Tomas M. Bartol ◽  
Côme Camus ◽  
Florian Levet ◽  
Ana Paula Menegolla ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Single Molecule ◽  
Glutamate Release ◽  
Neurotransmitter Receptors ◽  
Excitatory Synapses ◽  
Superresolution Microscopy ◽  
Synaptic Physiology ◽  
Transmission Properties ◽  
Presynaptic Release ◽  
Average Quantity

The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule superresolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs. mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.

scholarly journals Output-Specific Adaptation of Habenula-Midbrain Excitatory Synapses During Cocaine Withdrawal

2021 ◽  
Vol 13 ◽  
Author(s):  
Joseph Clerke ◽  
Patricia Preston-Ferrer ◽  
Ioannis S. Zouridis ◽  
Audrey Tissot ◽  
Laura Batti ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Glutamate Release ◽  
Synaptic Connectivity ◽  
Excitatory Synapses ◽  
Medial Aspect ◽  
Cocaine Withdrawal ◽  
Lateral Habenula ◽  
Specific Adaptation ◽  
Neuronal Populations ◽  
Presynaptic Release

Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations’ activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.

Interactions of Inhibition and Excitation in the Light-Evoked Currents of X Type Retinal Ganglion Cells

1998 ◽  
Vol 80 (6) ◽  
pp. 2975-2990 ◽  
Author(s):  
Ethan D. Cohen
Keyword(s):  
Retinal Ganglion Cells ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Cell Function ◽  
Ganglion Cells ◽  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Retinal Ganglion ◽  
Inhibitory Conductance ◽  
X Cells

Cohen, Ethan D. Interactions of inhibition and excitation in the light-evoked currents of X type retinal ganglion cells. J. Neurophysiol. 80: 2975–2990, 1998. The excitatory and inhibitory conductances driving the light-evoked currents (LECs) of cat and ferret on- and off-center X ganglion cells were examined in sliced and isolated retina preparations using center spot stimulation in tetrodotoxin (TTX)-containing Ringer. on-center X ganglion cells showed an increase in an excitatory conductance reversed positive to +20 mV during the spot stimulus. At spot offset, a transient inhibitory conductance was activated on many cells that reversed near E Cl. off-center X ganglion cells showed increases in a sustained inhibitory conductance that reversed near E Cl during spot stimulation. At spot offset, an excitatory conductance was activated that reversed positive to +20 mV. The light-evoked current kinetics of on- and off-center X cells to spot stimulation did not significantly differ in form from their Y cell counterparts in TTX Ringer. When inhibition was blocked, current-voltage relations of the light-evoked excitatory postsynaptic currents (EPSCs) of both on- and off-X cells were L-shaped and reversed near 0 mV. The EPSCs averaged between 300 and 500 pA at −80 mV. The metabotropic glutamate receptor agonist 2-amino-4-phosphonobutyric acid (APB), was used to block on-center bipolar cell function. The LECs of on-X ganglion cells were totally blocked in APB at all holding potentials. APB caused prominent reductions in the dark holding current and synaptic noise of on-X cells. In contrast, the LECs of off-X ganglion cells remained in APB. An increase in the dark holding current was observed. The excitatory amino acid receptor antagonist combination of d-amino-5-phosphono-pentanoic acid (d-AP5) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxalinedione (NBQX) was used to block ionotropic glutamate receptor retinal neurotransmission. The LECs of all on-X ganglion cells were totally blocked, and their holding currents were reduced similar to the actions of APB. For off-X ganglion cells, the antagonist combination always blocked the excitatory current at light-off; however, in many cells, the inhibitory current at light-on remained. on-center X ganglion cells receive active excitation during center illumination, and a transient inhibition at light-off. In contrast off-center X ganglion cells experience a sustained active inhibition during center illumination, and a shorter increase in excitation at light-offset. Cone bipolar cells provide a resting level of glutamate release on X ganglion cells on which their light-evoked currents are superimposed.

scholarly journals Glutamate, NMDA, and AMPA Induced Changes in Extracellular Space Volume and Tortuosity in the Rat Spinal Cord

2001 ◽  
Vol 21 (9) ◽  
pp. 1077-1089 ◽  
Author(s):  
Lýdia Vargová ◽  
Pavla Jendelová ◽  
Alexandr Chvátal ◽  
Eva Syková
Keyword(s):  
Spinal Cord ◽  
Glutamate Receptor ◽  
Extracellular Space ◽  
Volume Fraction ◽  
Glutamate Release ◽  
Extracellular Potassium ◽  
Receptor Agonists ◽  
Diffusion Parameters ◽  
Glutamate Receptor Agonists ◽  
Cellular Swelling

Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-d-aspartate (NMDA), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pHe), extracellular potassium concentration ([K+]e), and changes in extracellular space (ECS) diffusion parameters (volume fraction α, tortuosity λ) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K+]e, alkaline-acid shifts, a substantial decrease in α, and an increase in λ. After washout of the glutamate receptor agonists, α either returned to or overshot normal values, whereas λ remained elevated. Pretreatment with 20 mmol/L Mg++, MK801, or CNQX blocked the changes in diffusion parameters, [K+]e and pHe evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca2+-free solution, which had no effect on the [K+]e increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca2+]e-dependent decrease in α and increase in λ. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.

scholarly journals Glial Wingless/Wnt Regulates Glutamate Receptor Clustering and Synaptic Physiology at the Drosophila Neuromuscular Junction

2014 ◽  
Vol 34 (8) ◽  
pp. 2910-2920 ◽  
Author(s):  
K. S. Kerr ◽  
Y. Fuentes-Medel ◽  
C. Brewer ◽  
R. Barria ◽  
J. Ashley ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Glutamate Receptor ◽  
Receptor Clustering ◽  
Synaptic Physiology

scholarly journals Extraction of accurate cytoskeletal actin velocity distributions from noisy measurements

2020 ◽  
Author(s):  
Cayla M. Miller ◽  
Elgin Korkmazhan ◽  
Alexander R. Dunn
Keyword(s):  
Single Molecule ◽  
Actin Filaments ◽  
Dynamical Behavior ◽  
Jump Process ◽  
Pairwise Distance ◽  
Actin Dynamics ◽  
Cell Cortex ◽  
Superresolution Microscopy ◽  
Distance Distributions ◽  
Primary Fibroblasts

Dynamic remodeling of the actin cytoskeleton allows cells to migrate, change shape, and exert mechanical forces on their surroundings. How the complex dynamical behavior of the cytoskeleton arises from the interactions of its molecular components remains incompletely understood. Tracking the movement of individual actin filaments in living cells can in principle provide a powerful means of addressing this question. However, single-molecule fluorescence imaging measurements that could provide this information are limited by low signal-to-noise ratios, with the result that the localization errors for individual fluorophore fiducials attached to filamentous (F)-actin are comparable to the distances traveled by actin filaments between measurements. In this study we tracked the movement F-actin labeled with single-molecule densities of the fluorogenic label SiR-actin in primary fibroblasts and endothelial cells. We then used a Bayesian statistical approach to estimate true, underlying actin filament velocity distributions from the tracks of individual actin-associated fluorophores along with quantified localization uncertainties. This analysis approach is broadly applicable to inferring statistical pairwise distance distributions arising from noisy point localization measurements such as occur in superresolution microscopy. We found that F-actin velocity distributions were better described by a statistical jump process, in which filaments exist in mechanical equilibria punctuated by abrupt, jump-like movements, than by models incorporating combinations of diffusive motion and drift. A model with exponentially distributed time- and length-scales for filament jumps recapitulated F-actin velocity distributions measured for the cell cortex, integrin-based adhesions, and actin stress fibers, indicating that a common physical model can potentially describe F-actin dynamics in a variety of cellular contexts.

scholarly journals Monomers of AMPA-Type Glutamate Receptor Subunits Diffuse in and Out of Spines; Unraveling by Single-Molecule Tracking

2019 ◽  
Vol 116 (3) ◽  
pp. 529a
Author(s):  
Jyoji Morise ◽  
Kenichi G.N. Suzuki ◽  
Ayaka Kitagawa ◽  
Yoshihiko Wakazono ◽  
Kogo Takamiya ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Single Molecule ◽  
Single Molecule Tracking

scholarly journals Single-Molecule Imaging and Labelling with DNA-Based Superresolution Microscopy

2020 ◽  
Vol 118 (3) ◽  
pp. 146a
Author(s):  
Mingjie Dai ◽  
Ninning Liu ◽  
Sinem K. Saka ◽  
Peng Yin
Keyword(s):  
Single Molecule ◽  
Single Molecule Imaging ◽  
Superresolution Microscopy

Facilitated Glutamatergic Transmission in the Striatum of D2 Dopamine Receptor-Deficient Mice

2001 ◽  
Vol 85 (2) ◽  
pp. 659-670 ◽  
Author(s):  
C. Cepeda ◽  
R. S. Hurst ◽  
K. L. Altemus ◽  
J. Flores-Hernández ◽  
C. R. Calvert ◽  
...  
Keyword(s):  
Voltage Clamp ◽  
Glutamate Receptor ◽  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Synaptic Activity ◽  
Membrane Properties ◽  
Receptor Subtype ◽  
Da Receptors ◽  
Change In Mean ◽  
Deficient Mice

Dopamine (DA) receptors play an important role in the modulation of excitability and the responsiveness of neurons to activation of excitatory amino acid receptors in the striatum. In the present study, we utilized mice with genetic deletion of D2 or D4 DA receptors and their wild-type (WT) controls to examine if the absence of either receptor subtype affects striatal excitatory synaptic activity. Immunocytochemical analysis verified the absence of D2 or D4 protein expression in the striatum of receptor-deficient mutant animals. Sharp electrode current- and whole cell patch voltage-clamp recordings were obtained from slices of receptor-deficient and WT mice. Basic membrane properties were similar in D2 and D4 receptor-deficient mutants and their respective WT controls. In current-clamp recordings in WT animals, very little low-amplitude spontaneous synaptic activity was observed. The frequency of these spontaneous events was increased slightly in D2 receptor-deficient mice. In addition, large-amplitude depolarizations were observed in a subset of neurons from only the D2 receptor-deficient mutants. Bath application of the K+ channel blocker 4-aminopyridine (100 μM) and bicuculline methiodide (10 μM, to block synaptic activity due to activation of GABAA receptors) markedly increased spontaneous synaptic activity in receptor-deficient mutants and WTs. Under these conditions, D2 receptor-deficient mice displayed significantly more excitatory synaptic activity than their WT controls, while there was no difference between D4receptor-deficient mice and their controls. In voltage-clamp recordings, there was an increase in frequency of spontaneous glutamate receptor-mediated inward currents without a change in mean amplitude in D2 receptor-deficient mutants. In WT mice, activation of D2 family receptors with quinpirole decreased spontaneous excitatory events and conversely sulpiride, a D2 receptor antagonist, increased activity. In D2 receptor-deficient mice, sulpiride had very little net effect. Morphologically, a subpopulation of medium-sized spiny neurons from D2 receptor-deficient mice displayed decreased dendritic spines compared with cells from WT mice. These results provide evidence that D2 receptors play an important role in the regulation of glutamate receptor-mediated activity in the corticostriatal or thalamostriatal pathway. These receptors may function as gatekeepers of glutamate release or of its subsequent effects and thus may protect striatal neurons from excessive excitation.

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