scholarly journals Circadian modulation of neurons and astrocytes controls synaptic plasticity in hippocampal area CA1

2019 ◽  
Author(s):  
John P. McCauley ◽  
Maurice A. Petroccione ◽  
Lianna Y. D’Brant ◽  
Gabrielle C. Todd ◽  
Nurat Affinnih ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Temporal Dynamics ◽  
Rhythmic Activity ◽  
Surface Expression ◽  
Receptor Activation ◽  
Cellular Mechanisms ◽  
Functional Changes ◽  
Area Ca1 ◽  
Hippocampal Area

SummaryMost animal species operate according to a 24-hour period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN is known to modulate hippocampal-dependent memory processes, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we show that there are cell-type specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors, whereas astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learningin vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings identify important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus and alter the temporal dynamics of cognitive processing.

P1622Cancer drugs induce functional and structural impairment in adult cardiomyocytes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C Altomare ◽  
V Biemmi ◽  
E Torre ◽  
M Rocchetti ◽  
M Ferrandi ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Structural Changes ◽  
Decay Amplitude ◽  
Sampling Rate ◽  
Growth Factor Receptor ◽  
Cellular Mechanisms ◽  
Systolic Volume ◽  
Functional Changes ◽  
Time To Peak

Abstract Introduction The addition of anti-human epidermal growth factor receptor 2 (HER2; ErbB2) monoclonal antibody Trastuzumab (TRZ) to Doxorubicin (DOXO) chemotherapy is associated with a synergistic increase in cardiac toxicity. While previous studies have addressed the toxicity of both agents on isolated cardiomyocytes (CMs), little is known regarding this process in vivo, especially with respect to electrophysiological changes. Purpose To investigate electrical and structural changes in LV and RV CMs using an in vivo rat model of DOXO/TRZ cardiotoxicity. Methods Rats received 6 IP injections of either DOXO or TRZ over a 2-week period, or 6 doses of DOXO followed by 6 doses of TRZ (COMBO), or saline as a control. In-vivo echocardiography was performed. Electrical activity and Ca2+ handling were assessed in LV and RV CMs from rat hearts. Single cell patch-clamp and field stimulation experiments were performed. Spontaneous sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks) were recorded at x100 magnification in line-scan mode (sampling rate 0.7 kHz) from 2 μM Fluo4-AM loaded CMs. To assess T-tubular disarray, CMs were incubated with di-3-ANEPPDHQ and periodic component was quantified by Fast Fourier Transform (FFT) analysis of confocal microscopy images. Results DOXO, and to a greater extent COMBO treatment was associated with significant increases in both LV end-systolic and end-diastolic volumes, and decreases in LVEF and fractional shortening. By contrast, TRZ alone merely increased LV end-systolic volume. Electrophysiological studies showed increases in action potential duration (APD), beat-to-beat variability of repolarization (BVR), delayed after depolarizations (DADs), and Ca2+-sparks in both DOXO and COMBO groups. Stimulated intracellular Ca2+ transients (1,2 and 4 Hz) showed significant changes with respect to time to peak, tau decay, amplitude, and fractional release in the DOXO group. These changes were associated with a significant downregulation of sarco/endoplasmic reticulum Ca2+ ATPase pump (SERCA) expression. From a structural viewpoint, these changes were associated with T-tubular disarray in the DOXO and COMBO groups. Conclusions DOXO, and to a greater extent COMBO treatment (but not TRZ alone) cause LV dysfunction in vivo. Moreover, both DOXO and COMBO treatments, but not TRZ alone, induce electrophysiological abnormalities and both structural and functional changes in the sarcoplasmic reticulum. These findings provide novel insights into the cellular mechanisms of CM dysfunction and arrhythmias associated with combined DOXO/TRZ therapy. Acknowledgement/Funding Swiss League against Cancer

scholarly journals Functional Analysis of the Murine Cytomegalovirus Chemokine Receptor Homologue M33: Ablation of Constitutive Signaling Is Associated with an Attenuated Phenotype In Vivo

2007 ◽  
Vol 82 (4) ◽  
pp. 1884-1898 ◽  
Author(s):  
Ruth Case ◽  
Emma Sharp ◽  
Tau Benned-Jensen ◽  
Mette M. Rosenkilde ◽  
Nicholas Davis-Poynter ◽  
...  
Keyword(s):  
Cell Surface ◽  
Salivary Glands ◽  
Surface Expression ◽  
Receptor Activation ◽  
Murine Cytomegalovirus ◽  
Cell Surface Expression ◽  
Transmembrane Receptors ◽  
C Terminus ◽  
The Impact

ABSTRACT The murine cytomegalovirus (MCMV) M33 gene is conserved among all betaherpesviruses and encodes a homologue of seven-transmembrane receptors (7TMR) with the capacity for constitutive signaling. Previous studies have demonstrated that M33 is important for MCMV dissemination to or replication within the salivary glands. In this study, we probed N- and C-terminal regions of M33 as well as known 7TMR signature motifs in transmembrane (TM) II and TM III to determine the impact on cell surface expression, constitutive signaling, and in vivo phenotype. The region between amino acids R340 and A353 of the C terminus was found to be important for CREB- and NFAT-mediated signaling, although not essential for phosphatidylinositol turnover. Tagging or truncation of the N terminus of M33 resulted in loss of cell surface expression. Within TM II, an F79D mutation abolished constitutive signaling, demonstrating a role, as in other cellular and viral 7TMR, of TM II in receptor activation. In TM III, the arginine (but not the asparagine) residue of the NRY motif (the counterpart of the common DRY motif in cellular 7TMR) was found to be essential for constitutive signaling. Selected mutations incorporated into recombinant MCMV showed that disruption of constitutive signaling for a viral 7TMR homologue resulted in a reduced capacity to disseminate to or replicate in the salivary glands. In addition, HCMV UL33 was found to partially compensate for the lack of M33 in vivo, suggesting conserved biological roles of the UL33 gene family.

scholarly journals Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice

2014 ◽  
Vol 112 (8) ◽  
pp. 1916-1924 ◽  
Author(s):  
Guan Cao ◽  
Kristen M. Harris
Keyword(s):  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Sprague Dawley ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Cellular Mechanisms ◽  
Adult Rats ◽  
Area Ca1 ◽  
Hippocampal Area ◽  
Theta Burst

Hippocampal long-term potentiation (LTP) is a model system for studying cellular mechanisms of learning and memory. Recent interest in mechanisms underlying the advantage of spaced over massed learning has prompted investigation into the effects of distributed episodes of LTP induction. The amount of LTP induced in hippocampal area CA1 by one train (1T) of theta-burst stimulation (TBS) in young Sprague-Dawley rats was further enhanced by additional bouts of 1T given at 1-h intervals. However, in young Long-Evans (LE) rats, 1T did not initially saturate LTP. Instead, a stronger LTP induction paradigm using eight trains of TBS (8T) induced saturated LTP in hippocampal slices from both young and adult LE rats as well as adult mice. The saturated LTP induced by 8T could be augmented by another episode of 8T following an interval of at least 90 min. The success rate across animals and slices in augmenting LTP by an additional episode of 8T increased significantly with longer intervals between the first and last episodes, ranging from 0% at 30- and 60-min intervals to 13–66% at 90- to 180-min intervals to 90–100% at 240-min intervals. Augmentation above initially saturated LTP was blocked by the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovaleric acid (d-APV). These findings suggest that the strength of induction and interval between episodes of TBS, as well as the strain and age of the animal, are important components in the augmentation of LTP.

Mechanism of platelet functional changes and effects of anti-platelet agents on in vivo hemostasis under different gravity conditions

2010 ◽  
Vol 108 (5) ◽  
pp. 1241-1249 ◽  
Author(s):  
Suping Li ◽  
Quanwei Shi ◽  
Guanglei Liu ◽  
Weilin Zhang ◽  
Zhicheng Wang ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Surface Expression ◽  
Filamin A ◽  
Modeled Microgravity ◽  
Functional Changes ◽  
Cytoskeleton Reorganization ◽  
Intracellular Ca ◽  
Thrombotic Diseases ◽  
Platelet Functions

Serious thrombotic and hemorrhagic problems or even fatalities evoked by either microgravity or hypergravity occur commonly in the world. We recently reported that platelet functions are inhibited in microgravity environments and activated under high-G conditions, which reveals the pathogenesis for gravity change-related hemorrhagic and thrombotic diseases. However, the mechanisms of platelet functional variations under different gravity conditions remain unclear. In this study we show that the amount of filamin A coimmunoprecipitated with GPIbα was enhanced in platelets exposed to modeled microgravity and, in contrast, was reduced in 8 G-exposed platelets. Hypergravity induced actin filament formation and redistribution, whereas actin filaments were reduced in platelets treated with modeled microgravity. Furthermore, intracellular Ca2+ levels were elevated by hypergravity. Pretreatment of platelets with the cell-permeable Ca2+ chelator BAPTA-AM had no effect on cytoskeleton reorganization induced by hypergravity but significantly reduced platelet aggregation induced by ristocetin/hypergravity. Two anti-platelet agents, aspirin and tirofiban, effectively reversed the shortened tail bleeding time and reduced the death rate of mice exposed to hypergravity. Furthermore, the increased P-selectin surface expression was obviously reduced in platelets from mice treated with aspirin/hypergravity compared with those from mice treated with hypergravity alone. These data suggest that the actin cytoskeleton reorganization and intracellular Ca2+ level play key roles in the regulation of platelet functions in different gravitational environments. The results with anti-platelet agents not only further confirm the activation of platelets in vivo but also suggest a therapeutic potential for hypergravity-induced thrombotic diseases.

scholarly journals In Vivo Roles for Matrix Metalloproteinase-9 in Mature Hippocampal Synaptic Physiology and Plasticity

2007 ◽  
Vol 98 (1) ◽  
pp. 334-344 ◽  
Author(s):  
Ozlem Bozdagi ◽  
Vanja Nagy ◽  
Kimberly T. Kwei ◽  
George W. Huntley
Keyword(s):  
Synaptic Plasticity ◽  
Proteolytic Activity ◽  
Neutralizing Antibodies ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Synaptic Function ◽  
Loss Of Function ◽  
Adult Rats ◽  
Area Ca1

Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have well-known, mostly deleterious roles in remodeling after injury or stroke, but their role in nonpathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here we address the role of MMP-9 in hippocampal synaptic plasticity using both gain- and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of long-term potentiation (LTP) at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating nonpathological synaptic function and plasticity in mature hippocampus.

Cell-Permeable Scavengers of Superoxide Prevent Long-Term Potentiation in Hippocampal Area CA1

1998 ◽  
Vol 80 (1) ◽  
pp. 452-457 ◽  
Author(s):  
Eric Klann
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Manganese Porphyrin ◽  
Area Ca1 ◽  
Term Potentiation ◽  
Hippocampal Area ◽  
Nmda Receptor Activation

Klann, Eric. Cell-permeable scavengers of superoxide prevent long-term potentiation in hippocampal area CA1. J. Neurophysiol. 80: 452–457, 1998. Long-term potentiation (LTP) in hippocampal area CA1 is generally dependent on N-methyl-d-aspartate (NMDA) receptor activation. Reactive oxygen species (ROS), including superoxide, are produced in response to NMDA receptor activation in a number of brain regions, including the hipppocampus. In this study, two cell-permeable manganese porphyrin compounds that mimic superoxide dismutase (SOD) were used to determine whether production of superoxide is required for the induction of LTP in area CA1 of rat hippocampal slices. Incubation of hippocampal slices with either Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) or Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP) prevented the induction of LTP. Incubation of slices with either light-inactivated MnTBAP or light-inactivated MnTMPyP had no effect on induction of LTP. Neither MnTBAP nor MnTMPyP was able to reverse preestablished LTP. These observations suggest that production of superoxide occurs in response to LTP-inducing stimulation and that superoxide is necessary for the induction of LTP.

scholarly journals LTP- and LTD-inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo

Hippocampus ◽  
2010 ◽  
Vol 21 (12) ◽  
pp. 1290-1301 ◽  
Author(s):  
Eser Yilmaz-Rastoder ◽  
Takeaki Miyamae ◽  
Amy E. Braun ◽  
Edda Thiels
Keyword(s):  
Mrna Level ◽  
Area Ca1 ◽  
Hippocampal Area

scholarly journals Non-competitive androgen receptor inhibition in vitro and in vivo

2009 ◽  
Vol 106 (17) ◽  
pp. 7233-7238 ◽  
Author(s):  
Jeremy O. Jones ◽  
Eric C. Bolton ◽  
Yong Huang ◽  
Clementine Feau ◽  
R. Kiplin Guy ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Prostate Gland ◽  
Benign Prostatic Hypertrophy ◽  
Receptor Activation ◽  
Cellular Mechanisms ◽  
Competitive Antagonism ◽  
Receptor Inhibition ◽  
A Cell

Androgen receptor (AR) inhibitors are used to treat multiple human diseases, including hirsutism, benign prostatic hypertrophy, and prostate cancer, but all available anti-androgens target only ligand binding, either by reduction of available hormone or by competitive antagonism. New strategies are needed, and could have an important impact on therapy. One approach could be to target other cellular mechanisms required for receptor activation. In prior work, we used a cell-based assay of AR conformation change to identify non-ligand inhibitors of AR activity. Here, we characterize 2 compounds identified in this screen: pyrvinium pamoate, a Food and Drug Administration-approved drug, and harmol hydrochloride, a natural product. Each compound functions by a unique, non-competitive mechanism and synergizes with competitive antagonists to disrupt AR activity. Harmol blocks DNA occupancy by AR, whereas pyrvinium does not. Pyrvinium inhibits AR-dependent gene expression in the prostate gland in vivo, and induces prostate atrophy. These results highlight new therapeutic strategies to inhibit AR activity.

scholarly journals Emergence of functional subnetworks in layer 2/3 cortex induced by sequential spikes in vivo

2016 ◽  
Vol 113 (10) ◽  
pp. E1372-E1381 ◽  
Author(s):  
Taekeun Kim ◽  
Won Chan Oh ◽  
Joon Ho Choi ◽  
Hyung-Bae Kwon
Keyword(s):  
Pyramidal Neurons ◽  
Sensory Information ◽  
Receptor Activation ◽  
Mammalian Brain ◽  
Time Interval ◽  
Cellular Mechanisms ◽  
Calcium Calmodulin Dependent ◽  
Layer 2 ◽  
Cortical Circuit

During cortical circuit development in the mammalian brain, groups of excitatory neurons that receive similar sensory information form microcircuits. However, cellular mechanisms underlying cortical microcircuit development remain poorly understood. Here we implemented combined two-photon imaging and photolysis in vivo to monitor and manipulate neuronal activities to study the processes underlying activity-dependent circuit changes. We found that repeated triggering of spike trains in a randomly chosen group of layer 2/3 pyramidal neurons in the somatosensory cortex triggered long-term plasticity of circuits (LTPc), resulting in the increased probability that the selected neurons would fire when action potentials of individual neurons in the group were evoked. Significant firing pattern changes were observed more frequently in the selected group of neurons than in neighboring control neurons, and the induction was dependent on the time interval between spikes, N-methyl-D-aspartate (NMDA) receptor activation, and Calcium/calmodulin-dependent protein kinase II (CaMKII) activation. In addition, LTPc was associated with an increase of activity from a portion of neighboring neurons with different probabilities. Thus, our results demonstrate that the formation of functional microcircuits requires broad network changes and that its directionality is nonrandom, which may be a general feature of cortical circuit assembly in the mammalian cortex.

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