scholarly journals Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Stephanie Maynard ◽  
Philippe Rostaing ◽  
Natascha Schaefer ◽  
Olivier Gemin ◽  
Adrien Candat ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Light And Electron Microscopy ◽  
Quantitative Information ◽  
Ventral Horn ◽  
Molecular Organization ◽  
Spinal Cord Tissue ◽  
Molecular Architecture ◽  
Glycine Receptors ◽  
Molecular Arrangement ◽  
Sensory Processes

Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy (SR-CLEM). We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.

scholarly journals Identification of a stereotypic molecular arrangement of glycine receptors at native spinal cord synapses

2021 ◽  
Author(s):  
Stephanie A Maynard ◽  
Philippe Rostaing ◽  
Olivier Gemin ◽  
Adrien Candat ◽  
Andréa Dumoulin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Light And Electron Microscopy ◽  
Quantitative Information ◽  
Ventral Horn ◽  
Molecular Organization ◽  
Spinal Cord Tissue ◽  
Molecular Architecture ◽  
Glycine Receptors ◽  
Molecular Arrangement ◽  
Sensory Processes

AbstractPrecise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brain stem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in native spinal cord tissue using quantitative super-resolution correlative light and electron microscopy (SR-CLEM). We show that GlyRs exhibit equal receptor-scaffold occupancy and constant absolute packing densities of about 2000 GlyRs µm−2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory PSDs rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks.

scholarly journals IKVAV-Containing Cell Membrane Penetrating Peptide Treatment Induces Changes in Cellular Morphology after Spinal Cord Injury

2016 ◽  
Vol 10 (11) ◽  
pp. 149 ◽  
Author(s):  
Soheila Kazemi ◽  
Wendy Baltzer ◽  
Hadi Mansouri ◽  
Karl Schilke ◽  
John Mata
Keyword(s):  
Spinal Cord ◽  
Cell Membrane ◽  
Motor Neurons ◽  
Light And Electron Microscopy ◽  
Cellular Morphology ◽  
Control Group ◽  
Spinal Cord Tissue ◽  
Compression Injury ◽  
Cord Injury ◽  
Membrane Spanning

A cell membrane spanning peptide was used to increase the concentration of the IKVAV motif within damaged mouse spinal cord tissue. This peptide was injected directly to the lesion 24 hours after spinal cord compression injury. Because the membrane-spanning portion of the peptide adheres to tissue upon injection with a long half-life we hypothesized that the bioactive IKVAV sequence will provide a sustained regenerative signal at the sight of injury. Five different groups of mice were used and cellular morphology observations were undertaken using light and electron microscopy. Three surgical control groups: IKVAV, peptide and mannitol; one surgical treatment group: IKVAV-peptide; and one non-surgical control group: normal, were used in this experiment. In this study, treatment with IKVAV-peptide after SCI resulted in an increased number of protoplasmic astrocytes, large active motor neurons, and regeneration of muscle bundles followed by behavioral improvement. In this paper, we describe the cellular differences between all groups.

Control of blood flow in the cat spinal cord

1983 ◽  
Vol 58 (5) ◽  
pp. 742-748 ◽  
Author(s):  
Oscar U. Scremin ◽  
Emilio E. Decima
Keyword(s):  
Spinal Cord ◽  
Blood Flow ◽  
White Matter ◽  
Ventral Horn ◽  
Hydrogen Gas ◽  
Lumbar Spinal Cord ◽  
Spinal Cord Tissue ◽  
Spinal Cord Blood Flow ◽  
Content Type ◽  
Fine Print

✓ Spinal cord blood flow (SCBF) and the effect of end-tidal CO2 concentration (ETCO2) on SCBF (CO2 reactivity) were studied in the lumbar spinal cord of cats by means of the hydrogen-clearance technique. Hydrogen gas was administered by inhalation, and its level in spinal cord tissue was estimated amperometrically with small (75 µm) platinum electrodes. The average SCBF's at normocapnia (ETCO2 = 4%) of the ventral horn gray matter and of the white matter at several locations were 43.2 and 16.2 ml·100 gm−1·min−1, respectively. For gray and white matter, the values of CO2 reactivity, estimated by the coefficient of the regression of SCBF (ml·100 gm−1·min−1) on ETCO2 (ml·100 ml−1) were 11.6 and 2.1, respectively. No differences in SCBF or CO2 reactivity were observed between intact animals kept under N2O-O2 ventilation and decerebrated animals with no anesthesia. After an acute spinal section, ventral horn SCBF and CO2 reactivity (measured eight segments below the cordotomy) were not altered, in spite of the profound neural depression present (that is, spinal shock). Orthodromic (dorsal root) stimulation of the ventral horn neurons induced an average increase in blood flow of 128% above control values. Antidromic (ventral root) motoneuron activation failed to produce any significant changes in ventral horn blood flow.

scholarly journals Characterization of ultrasound-mediated delivery of trastuzumab to normal and pathologic spinal cord tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paige Smith ◽  
Natalia Ogrodnik ◽  
Janani Satkunarajah ◽  
Meaghan A. O’Reilly
Keyword(s):  
Drug Delivery ◽  
Spinal Cord ◽  
Focused Ultrasound ◽  
Healthy Tissue ◽  
Spinal Cord Tissue ◽  
Sprague Dawley ◽  
Intense Staining ◽  
Her2 Breast Cancer ◽  
Sprague Dawley Rats ◽  
Blood Spinal Cord Barrier

AbstractExtensive studies on focused ultrasound (FUS)-mediated drug delivery through the blood–brain barrier have been published, yet little work has been published on FUS-mediated drug delivery through the blood-spinal cord barrier (BSCB). This work aims to quantify the delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and characterize its distribution within a model of leptomeningeal metastases. 10 healthy Sprague–Dawley rats were treated with FUS + trastuzumab and sacrificed at 2-h or 24-h post-FUS. A human IgG ELISA (Abcam) was used to measure trastuzumab concentration and a 12 ± fivefold increase was seen in treated tissue over control tissue at 2 h versus no increase at 24 h. Three athymic nude rats were inoculated with MDA-MB-231-H2N HER2 + breast cancer cells between the meninges in the thoracic region of the spinal cord and treated with FUS + trastuzumab. Immunohistochemistry was performed to visualize trastuzumab delivery, and semi-quantitative analysis revealed similar or more intense staining in tumor tissue compared to healthy tissue suggesting a comparable or greater concentration of trastuzumab was achieved. FUS can increase the permeability of the BSCB, improving drug delivery to specifically targeted regions of healthy and pathologic tissue in the spinal cord. The achieved concentrations within the healthy tissue are comparable to those reported in the brain.

scholarly journals Spinal Cord Repair: From Cells and Tissue Engineering to Extracellular Vesicles

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1872
Author(s):  
Shaowei Guo ◽  
Idan Redenski ◽  
Shulamit Levenberg
Keyword(s):  
Spinal Cord ◽  
Tissue Engineering ◽  
Extracellular Vesicles ◽  
Functional Recovery ◽  
Three Dimensional ◽  
Therapeutic Modality ◽  
Spinal Cord Tissue ◽  
New Paradigm ◽  
Cord Injury ◽  
Severe Motor

Spinal cord injury (SCI) is a debilitating condition, often leading to severe motor, sensory, or autonomic nervous dysfunction. As the holy grail of regenerative medicine, promoting spinal cord tissue regeneration and functional recovery are the fundamental goals. Yet, effective regeneration of injured spinal cord tissues and promotion of functional recovery remain unmet clinical challenges, largely due to the complex pathophysiology of the condition. The transplantation of various cells, either alone or in combination with three-dimensional matrices, has been intensively investigated in preclinical SCI models and clinical trials, holding translational promise. More recently, a new paradigm shift has emerged from cell therapy towards extracellular vesicles as an exciting “cell-free” therapeutic modality. The current review recapitulates recent advances, challenges, and future perspectives of cell-based spinal cord tissue engineering and regeneration strategies.

Neuropeptide imaging in rat spinal cord with MALDI-TOF MS: Method development for the application in pain-related disease studies

2017 ◽  
Vol 23 (3) ◽  
pp. 105-115 ◽  
Author(s):  
Ping Sui ◽  
Hiroyuki Watanabe ◽  
Konstantin Artemenko ◽  
Wei Sun ◽  
Georgy Bakalkin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Method Development ◽  
Imaging Mass Spectrometry ◽  
Small Animal ◽  
Spinal Cord Tissue ◽  
Rat Spinal Cord ◽  
Maldi Tof Ms ◽  
Maldi Tof ◽  
Imaging Result ◽  
Tof Ms

Spinal cord as a connection between brain and peripheral nervous system is an essential material for studying neural transmission, especially in pain-related research. This study was the first to investigate pain-related neuropeptide distribution in rat spinal cord using a matrix-assisted laser desorption ionization-time of flight imaging mass spectrometry (MALDI TOF MS) approach. The imaging workflow was evaluated and showed that MALDI TOF MS provides efficient resolution and robustness for neuropeptide imaging in rat spinal cord tissue. The imaging result showed that in naive rat spinal cord the molecular distribution of haeme, phosphatidylcholine, substance P and thymosin beta 4 were well in line with histological features. Three groups of pain-related neuropeptides, which are cleaved from prodynorphin, proenkephalin and protachykinin-1 proteins were detected. All these neuropeptides were found predominantly localized in the dorsal spinal cord and each group had unique distribution pattern. This study set the stage for future MALDI TOF MS application to elucidate signalling mechanism of pain-related diseases in small animal models.

Distribution of substance P in the spinal cord of patients with syringomyelia

1996 ◽  
Vol 84 (6) ◽  
pp. 992-998 ◽  
Author(s):  
Thomas H. Milhorat ◽  
Harrison T. M. Mu ◽  
Carole C. LaMotte ◽  
Ade T. Milhorat
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Dorsal Horn ◽  
Ventral Horn ◽  
Immunohistochemical Method ◽  
Positive Staining ◽  
Content Type ◽  
Normal Individuals ◽  
Neurologically Normal ◽  
Intermediolateral Nucleus

✓ The distribution of substance P, a putative neurotransmitter and pain-related peptide, was studied using the peroxidase—antiperoxidase immunohistochemical method in the spinal cords obtained from autopsy of 10 patients with syringomyelia and 10 age- and sex-matched, neurologically normal individuals. Substance P immunoreactivity was present in axons and in terminal-like processes in close apposition to neurons in the first, second, and third laminae of the dorsal horn. Smaller amounts of peroxidase-positive staining were found in the fifth lamina of the dorsal horn, the intermediolateral nucleus, the intermediomedial nucleus, and the ventral horn. In nine of 10 patients with syringomyelia, there was a substantial increase in substance P immunoreactivity in the first, second, third, and fifth laminae below the level of the lesion. A marked reduction or absence of staining was present in segments of the spinal cord occupied by the syrinx. Central cavities produced bilateral abnormalities, whereas eccentric cavities produced changes that were ipsilateral to the lesion. No alterations in staining were found in the spinal cord of an asymptomatic patient with a small central syrinx. The authors conclude that syringomyelia can be associated with abnormalities in spinal cord levels of substance P, which may affect the modulation and perception of pain.

scholarly journals Modulation of spinal motor networks by astrocyte-derived adenosine is dependent on D1-like dopamine receptor signaling

2018 ◽  
Vol 120 (3) ◽  
pp. 998-1009 ◽  
Author(s):  
David Acton ◽  
Matthew J. Broadhead ◽  
Gareth B. Miles
Keyword(s):  
Spinal Cord ◽  
Protein Kinase ◽  
Dopamine Receptor ◽  
Kinase Inhibitor ◽  
Ventral Horn ◽  
Skf 38393 ◽  
Network Activity ◽  
Related Activity ◽  
Burst Frequency ◽  
Spinal Motor

Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behavior. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysis of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signaling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways. Here, we demonstrate that adenosine produced upon astrocytic stimulation modulates locomotor-related activity by counteracting the excitatory effects of D1LR signaling and does not act by previously described dopamine-independent pathways. In spinal cord preparations from postnatal mice, a D1LR agonist, SKF 38393, increased the frequency of locomotor-related bursting induced by 5-hydroxytryptamine and N-methyl-d-aspartate. Bath-applied adenosine reduced burst frequency only in the presence of SKF 38393, as did adenosine produced after activation of protease-activated receptor-1 to stimulate astrocytes. Furthermore, the A1R antagonist 8-cyclopentyl-1,3-dipropylxanthine enhanced burst frequency only in the presence of SKF 38393, indicating that endogenous adenosine produced by astrocytes during network activity also acts by modulating D1LR signaling. Finally, modulation of bursting by adenosine released upon stimulation of astrocytes was blocked by protein kinase inhibitor-(14–22) amide, a protein kinase A (PKA) inhibitor, consistent with A1R-mediated antagonism of the D1LR/adenylyl cyclase/PKA pathway. Together, these findings support a novel, astrocytic mechanism of metamodulation within the mammalian spinal cord, highlighting the complexity of the molecular interactions that specify motor output. NEW & NOTEWORTHY Astrocytes within the spinal cord produce adenosine during ongoing locomotor-related activity or when experimentally stimulated. Here, we show that adenosine derived from astrocytes acts at A1 receptors to inhibit a pathway by which D1-like receptors enhance the frequency of locomotor-related bursting. These data support a novel form of metamodulation within the mammalian spinal cord, enhancing our understanding of neuron-astrocyte interactions and their importance in shaping network activity.

A new dopaminergic terminal plexus in the ventral horn of rat spinal cord

1989 ◽  
Vol 9 ◽  
pp. 141
Author(s):  
Muneyasu Shirouzu ◽  
Takehiko Anraku ◽  
Yoshifumi Iwashita ◽  
Masami Yoshida
Keyword(s):  
Spinal Cord ◽  
Ventral Horn ◽  
Rat Spinal Cord ◽  
Dopaminergic Terminal
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