Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male-Male Social Interaction.

PubMed

Cansler, Hillary L; Maksimova, Marina A; Meeks, Julian P

2017-07-26

Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male-male social experience. Following the resident-intruder paradigm, Arc -expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc -expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated I H currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc -expressing interneurons. SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male-male social chemosensory encounters. We show that the plasticity-associated immediate-early gene Arc is selectively expressed in IGCs from resident males following the resident-intruder assay. After behavior, Arc -expressing IGCs are more strongly excited by sensory input stimulation and MC activation is suppressed. Arc -expressing IGCs do not show increased excitatory synaptic drive but instead show increased intrinsic excitability. These data indicate that MC-IGC plasticity is induced after male-male social chemosensory encounters, resulting in enhanced MC suppression by Arc -expressing IGCs. Copyright © 2017 the authors 0270-6474/17/377240-13$15.00/0.

Experience-Dependent Plasticity in Accessory Olfactory Bulb Interneurons following Male–Male Social Interaction

PubMed Central

Maksimova, Marina A.

2017-01-01

Chemosensory information processing in the mouse accessory olfactory system guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC–interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe targeted electrophysiological studies of AOB inhibitory internal granule cells (IGCs), many of which upregulate the immediate-early gene Arc after male–male social experience. Following the resident–intruder paradigm, Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than nonexpressing neighbors when sensory inputs were stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident–intruder encounters. These results reveal that nonmating behaviors drive AOB inhibitory plasticity and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons. SIGNIFICANCE STATEMENT The accessory olfactory bulb (AOB) is a site of experience-dependent plasticity between excitatory mitral cells (MCs) and inhibitory internal granule cells (IGCs), but the physiological mechanisms and behavioral conditions driving this plasticity remain unclear. Here, we report studies of AOB neuronal plasticity following male–male social chemosensory encounters. We show that the plasticity-associated immediate-early gene Arc is selectively expressed in IGCs from resident males following the resident–intruder assay. After behavior, Arc-expressing IGCs are more strongly excited by sensory input stimulation and MC activation is suppressed. Arc-expressing IGCs do not show increased excitatory synaptic drive but instead show increased intrinsic excitability. These data indicate that MC–IGC plasticity is induced after male–male social chemosensory encounters, resulting in enhanced MC suppression by Arc-expressing IGCs. PMID:28659282

Tunicamycin impairs olfactory learning and synaptic plasticity in the olfactory bulb.

PubMed

Tong, Jia; Okutani, Fumino; Murata, Yoshihiro; Taniguchi, Mutsuo; Namba, Toshiharu; Wang, Yu-Jie; Kaba, Hideto

2017-03-06

Tunicamycin (TM) induces endoplasmic reticulum (ER) stress and inhibits N-glycosylation in cells. ER stress is associated with neuronal death in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and most patients complain of the impairment of olfactory recognition. Here we examined the effects of TM on aversive olfactory learning and the underlying synaptic plasticity in the main olfactory bulb (MOB). Behavioral experiments demonstrated that the intrabulbar infusion of TM disabled aversive olfactory learning without affecting short-term memory. Histological analyses revealed that TM infusion upregulated C/EBP homologous protein (CHOP), a marker of ER stress, in the mitral and granule cell layers of MOB. Electrophysiological data indicated that TM inhibited tetanus-induced long-term potentiation (LTP) at the dendrodendritic excitatory synapse from mitral to granule cells. A low dose of TM (250nM) abolished the late phase of LTP, and a high dose (1μM) inhibited the early and late phases of LTP. Further, high-dose, but not low-dose, TM reduced the paired-pulse facilitation ratio, suggesting that the inhibitory effects of TM on LTP are partially mediated through the presynaptic machinery. Thus, our results support the hypothesis that TM-induced ER stress impairs olfactory learning by inhibiting synaptic plasticity via presynaptic and postsynaptic mechanisms in MOB. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Activity Regulates Functional Connectivity from the Vomeronasal Organ to the Accessory Olfactory Bulb

PubMed Central

Hovis, Kenneth R.; Ramnath, Rohit; Dahlen, Jeffrey E.; Romanova, Anna L.; LaRocca, Greg; Bier, Mark E.; Urban, Nathaniel N.

2012-01-01

The mammalian accessory olfactory system is specialized for the detection of chemicals that identify kin and conspecifics. Vomeronasal sensory neurons (VSNs), residing in the vomeronasal organ, project axons to the accessory olfactory bulb (AOB) where they form synapses with principle neurons, known as mitral cells. The organization of this projection is quite precise and is believed to be essential for appropriate function of this system. However, how this precise connectivity is established is unknown. We show here that in mice the vomeronasal duct is open at birth, allowing external chemical stimuli access to sensory neurons, and that these sensory neurons are capable of releasing neurotransmitter to downstream neurons as early as the first post-natal day. Using major histocompatibility complex class I (MHC-1) peptides to activate a selective subset of VSNs during the first few post-natal days of development, we show that increased activity results in exuberant VSN axonal projections and a delay in axonal coalescence into well-defined glomeruli in the AOB. Finally, we show that mitral cell dendritic refinement occurs just after the coalescence of pre-synaptic axons. Such a mechanism may allow the formation of precise connectivity with specific glomeruli that receive input from sensory neurons expressing the same receptor type. PMID:22674266

Electrophysiological mapping of the accessory olfactory bulb of the rabbit (Oryctolagus cuniculus).

PubMed

van Groen, T; Ruardy, L; da Silva, F H

1986-07-01

Field potentials elicited by electrical stimulation of the vomeronasal nerve were measured in the accessory olfactory bulb of the rabbit. Maps were made of the distribution of surface field potentials and of the corresponding depth profiles. The surface maps followed closely the contours of the accessory olfactory bulb: at the frontal border the field potential tended to zero and at the center of the structure the field potential attained a maximum. Depth profiles of the field potentials through the accessory olfactory bulb presented a surface-negative wave and, in depth, a positive wave. The polarity reversal occurred at the deep part of the granule cell layer. The zero equipotential line followed closely the curvature of the granule cell layer. Current source density analysis of the depth profiles revealed a main sink at the external plexiform and granule cell layers. This indicates that the main activity in the accessory olfactory bulb is generated by the synapses between the mitral cells and the granule cells as is found in the main olfactory bulb.

Implementation of olfactory bulb glomerular-layer computations in a digital neurosynaptic core.

PubMed

Imam, Nabil; Cleland, Thomas A; Manohar, Rajit; Merolla, Paul A; Arthur, John V; Akopyan, Filipp; Modha, Dharmendra S

2012-01-01

We present a biomimetic system that captures essential functional properties of the glomerular layer of the mammalian olfactory bulb, specifically including its capacity to decorrelate similar odor representations without foreknowledge of the statistical distributions of analyte features. Our system is based on a digital neuromorphic chip consisting of 256 leaky-integrate-and-fire neurons, 1024 × 256 crossbar synapses, and address-event representation communication circuits. The neural circuits configured in the chip reflect established connections among mitral cells, periglomerular cells, external tufted cells, and superficial short-axon cells within the olfactory bulb, and accept input from convergent sets of sensors configured as olfactory sensory neurons. This configuration generates functional transformations comparable to those observed in the glomerular layer of the mammalian olfactory bulb. Our circuits, consuming only 45 pJ of active power per spike with a power supply of 0.85 V, can be used as the first stage of processing in low-power artificial chemical sensing devices inspired by natural olfactory systems.

The Slow Dynamics of Intracellular Sodium Concentration Increase the Time Window of Neuronal Integration: A Simulation Study

PubMed Central

Zylbertal, Asaph; Yarom, Yosef; Wagner, Shlomo

2017-01-01

Changes in intracellular Na+ concentration ([Na+]i) are rarely taken into account when neuronal activity is examined. As opposed to Ca2+, [Na+]i dynamics are strongly affected by longitudinal diffusion, and therefore they are governed by the morphological structure of the neurons, in addition to the localization of influx and efflux mechanisms. Here, we examined [Na+]i dynamics and their effects on neuronal computation in three multi-compartmental neuronal models, representing three distinct cell types: accessory olfactory bulb (AOB) mitral cells, cortical layer V pyramidal cells, and cerebellar Purkinje cells. We added [Na+]i as a state variable to these models, and allowed it to modulate the Na+ Nernst potential, the Na+-K+ pump current, and the Na+-Ca2+ exchanger rate. Our results indicate that in most cases [Na+]i dynamics are significantly slower than [Ca2+]i dynamics, and thus may exert a prolonged influence on neuronal computation in a neuronal type specific manner. We show that [Na+]i dynamics affect neuronal activity via three main processes: reduction of EPSP amplitude in repeatedly active synapses due to reduction of the Na+ Nernst potential; activity-dependent hyperpolarization due to increased activity of the Na+-K+ pump; specific tagging of active synapses by extended Ca2+ elevation, intensified by concurrent back-propagating action potentials or complex spikes. Thus, we conclude that [Na+]i dynamics should be considered whenever synaptic plasticity, extensive synaptic input, or bursting activity are examined. PMID:28970791

Parallel processing of afferent olfactory sensory information

PubMed Central

Vaaga, Christopher E.

2016-01-01

Key points The functional synaptic connectivity between olfactory receptor neurons and principal cells within the olfactory bulb is not well understood.One view suggests that mitral cells, the primary output neuron of the olfactory bulb, are solely activated by feedforward excitation.Using focal, single glomerular stimulation, we demonstrate that mitral cells receive direct, monosynaptic input from olfactory receptor neurons.Compared to external tufted cells, mitral cells have a prolonged afferent‐evoked EPSC, which serves to amplify the synaptic input.The properties of presynaptic glutamate release from olfactory receptor neurons are similar between mitral and external tufted cells.Our data suggest that afferent input enters the olfactory bulb in a parallel fashion. Abstract Primary olfactory receptor neurons terminate in anatomically and functionally discrete cortical modules known as olfactory bulb glomeruli. The synaptic connectivity and postsynaptic responses of mitral and external tufted cells within the glomerulus may involve both direct and indirect components. For example, it has been suggested that sensory input to mitral cells is indirect through feedforward excitation from external tufted cells. We also observed feedforward excitation of mitral cells with weak stimulation of the olfactory nerve layer; however, focal stimulation of an axon bundle entering an individual glomerulus revealed that mitral cells receive monosynaptic afferent inputs. Although external tufted cells had a 4.1‐fold larger peak EPSC amplitude, integration of the evoked currents showed that the synaptic charge was 5‐fold larger in mitral cells, reflecting the prolonged response in mitral cells. Presynaptic afferents onto mitral and external tufted cells had similar quantal amplitude and release probability, suggesting that the larger peak EPSC in external tufted cells was the result of more synaptic contacts. The results of the present study indicate that the monosynaptic afferent input to mitral cells depends on the strength of odorant stimulation. The enhanced spiking that we observed in response to brief afferent input provides a mechanism for amplifying sensory information and contrasts with the transient response in external tufted cells. These parallel input paths may have discrete functions in processing olfactory sensory input. PMID:27377344

Olfactory epithelium influences the orientation of mitral cell dendrites during development.

PubMed

López-Mascaraque, Laura; García, Concepción; Blanchart, Albert; De Carlos, Juan A

2005-02-01

We have established previously that, although the olfactory epithelium is absent in the homozygous Pax-6 mutant mouse, an olfactory bulb-like structure (OBLS) does develop. Moreover, this OBLS contains cells that correspond to mitral cells, the primary projection neurons in the olfactory bulb. The current study aimed to address whether the dendrites of mitral cells in the olfactory bulb or in the OBLS mitral-like cells, exhibit a change in orientation in the presence of the olfactory epithelium. The underlying hypothesis is that the olfactory epithelium imparts a trophic signal on mitral and mitral-like cell that influences the growth of their primary dendrites, orientating them toward the surface of the olfactory bulb. Hence, we cultured hemibrains from wild-type and Pax 6 mutant mice from two different embryonic stages (embryonic days 14 and 15) either alone or in coculture with normal olfactory epithelial explants or control tissue (cerebellum). Our results indicate that the final dendritic orientation of mitral and mitral-like cells is directly influenced both by age and indeed by the presence of the olfactory epithelium. Copyright 2004 Wiley-Liss, Inc.

Intraglomerular inhibition maintains mitral cell response contrast across input frequencies

PubMed Central

Shao, Zuoyi; Puche, Adam C.

2013-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can “sharpen” MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain “contrast” in MC encoding during sniff-sampled inputs. PMID:23926045

Intraglomerular inhibition maintains mitral cell response contrast across input frequencies.

PubMed

Shao, Zuoyi; Puche, Adam C; Shipley, Michael T

2013-11-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MTCs) and external tufted cells (ETCs); ETCs provide additional feed-forward excitation to MTCs. Both are strongly regulated by intraglomerular inhibition that can last up to 1 s and, when blocked, dramatically increases ON-evoked MC spiking. Intraglomerular inhibition thus limits the magnitude and duration of MC spike responses to sensory input. In vivo, sensory input is repetitive, dictated by sniffing rates from 1 to 8 Hz, potentially summing intraglomerular inhibition. To investigate this, we recorded MTC responses to 1- to 8-Hz ON stimulation in slices. Inhibitory postsynaptic current area (charge) following each ON stimulation was unchanged from 1 to 5 Hz and modestly paired-pulse attenuated at 8 Hz, suggesting there is no summation and only limited decrement at the highest input frequencies. Next, we investigated frequency independence of intraglomerular inhibition on MC spiking. MCs respond to single ON shocks with an initial spike burst followed by reduced spiking decaying to baseline. Upon repetitive ON stimulation peak spiking is identical across input frequencies but the ratio of peak-to-minimum rate before the stimulus (max-min) diminishes from 30:1 at 1 Hz to 15:1 at 8 Hz. When intraglomerular inhibition is selectively blocked, peak spike rate is unchanged but trough spiking increases markedly decreasing max-min firing ratios from 30:1 at 1 Hz to 2:1 at 8 Hz. Together, these results suggest intraglomerular inhibition is relatively frequency independent and can "sharpen" MC responses to input across the range of frequencies. This suggests that glomerular circuits can maintain "contrast" in MC encoding during sniff-sampled inputs.

Discharge patterning in rat olfactory bulb mitral cells in vivo

PubMed Central

Leng, Gareth; Hashimoto, Hirofumi; Tsuji, Chiharu; Sabatier, Nancy; Ludwig, Mike

2014-01-01

Abstract Here we present a detailed statistical analysis of the discharge characteristics of mitral cells of the main olfactory bulb of urethane‐anesthetized rats. Neurons were recorded from the mitral cell layer, and antidromically identified by stimuli applied to the lateral olfactory tract. All mitral cells displayed repeated, prolonged bursts of action potentials typically lasting >100 sec and separated by similarly long intervals; about half were completely silent between bursts. No such bursting was observed in nonmitral cells recorded in close proximity to mitral cells. Bursts were asynchronous among even adjacent mitral cells. The intraburst activity of most mitral cells showed strong entrainment to the spontaneous respiratory rhythm; similar entrainment was seen in some, but not all nonmitral cells. All mitral cells displayed a peak of excitability at ~25 msec after spikes, as reflected by a peak in the interspike interval distribution and in the corresponding hazard function. About half also showed a peak at about 6 msec, reflecting the common occurrence of doublet spikes. Nonmitral cells showed no such doublet spikes. Bursts typically increased in intensity over the first 20–30 sec of a burst, during which time doublets were rare or absent. After 20–30 sec (in cells that exhibited doublets), doublets occurred frequently for as long as the burst persisted, in trains of up to 10 doublets. The last doublet was followed by an extended relative refractory period the duration of which was independent of train length. In cells that were excited by application of a particular odor, responsiveness was apparently greater during silent periods between bursts than during bursts. Conversely in cells that were inhibited by a particular odor, responsiveness was only apparent when cells were active. Extensive raw (event timing) data from the cells, together with details of those analyses, are provided as supplementary material, freely available for secondary use by others. PMID:25281614

Cerebellins are differentially expressed in selective subsets of neurons throughout the brain.

PubMed

Seigneur, Erica; Südhof, Thomas C

2017-10-15

Cerebellins are secreted hexameric proteins that form tripartite complexes with the presynaptic cell-adhesion molecules neurexins or 'deleted-in-colorectal-cancer', and the postsynaptic glutamate-receptor-related proteins GluD1 and GluD2. These tripartite complexes are thought to regulate synapses. However, cerebellins are expressed in multiple isoforms whose relative distributions and overall functions are not understood. Three of the four cerebellins, Cbln1, Cbln2, and Cbln4, autonomously assemble into homohexamers, whereas the Cbln3 requires Cbln1 for assembly and secretion. Here, we show that Cbln1, Cbln2, and Cbln4 are abundantly expressed in nearly all brain regions, but exhibit strikingly different expression patterns and developmental dynamics. Using newly generated knockin reporter mice for Cbln2 and Cbln4, we find that Cbln2 and Cbln4 are not universally expressed in all neurons, but only in specific subsets of neurons. For example, Cbln2 and Cbln4 are broadly expressed in largely non-overlapping subpopulations of excitatory cortical neurons, but only sparse expression was observed in excitatory hippocampal neurons of the CA1- or CA3-region. Similarly, Cbln2 and Cbln4 are selectively expressed, respectively, in inhibitory interneurons and excitatory mitral projection neurons of the main olfactory bulb; here, these two classes of neurons form dendrodendritic reciprocal synapses with each other. A few brain regions, such as the nucleus of the lateral olfactory tract, exhibit astoundingly high Cbln2 expression levels. Viewed together, our data show that cerebellins are abundantly expressed in relatively small subsets of neurons, suggesting specific roles restricted to subsets of synapses. © 2017 Wiley Periodicals, Inc.

HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

PubMed Central

Deng, Jing; Mitsuki, Yu-ya; Shen, Guomiao; Ray, Jocelyn C.; Cicala, Claudia; Arthos, James; Dustin, Michael L.

2016-01-01

ABSTRACT HIV is transmitted most efficiently from cell to cell, and productive infection occurs mainly in activated CD4 T cells. It is postulated that HIV exploits immunological synapses formed between CD4 T cells and antigen-presenting cells to facilitate the targeting and infection of activated CD4 T cells. This study sought to evaluate how the presence of the HIV envelope (Env) in the CD4 T cell immunological synapse affects synapse formation and intracellular signaling to impact the downstream T cell activation events. CD4 T cells were applied to supported lipid bilayers that were reconstituted with HIV Env gp120, anti-T cell receptor (anti-TCR) monoclonal antibody, and ICAM-1 to represent the surface of HIV Env-bearing antigen-presenting cells. The results showed that the HIV Env did not disrupt immunological synapse formation. Instead, the HIV Env accumulated with TCR at the center of the synapse, altered the kinetics of TCR recruitment to the synapse and affected synapse morphology over time. The HIV Env also prolonged Lck phosphorylation at the synapse and enhanced TCR-induced CD69 upregulation, interleukin-2 secretion, and proliferation to promote virus infection. These results suggest that HIV uses the immunological synapse as a conduit not only for selective virus transmission to activated CD4 T cells but also for boosting the T cell activation state, thereby increasing its likelihood of undergoing productive replication in targeted CD4 T cells. IMPORTANCE There are about two million new HIV infections every year. A better understanding of how HIV is transmitted to susceptible cells is critical to devise effective strategies to prevent HIV infection. Activated CD4 T cells are preferentially infected by HIV, although how this is accomplished is not fully understood. This study examined whether HIV co-opts the normal T cell activation process through the so-called immunological synapse. We found that the HIV envelope is recruited to the center of the immunological synapse together with the T cell receptor and enhances the T cell receptor-induced activation of CD4 T cells. Heightened cellular activation promotes the capacity of CD4 T cells to support productive HIV replication. This study provides evidence of the exploitation of the normal immunological synapse and T cell activation process by HIV to boost the activation state of targeted CD4 T cells and promote the infection of these cells. PMID:27630246

WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts.

PubMed

Malinova, Dessislava; Fritzsche, Marco; Nowosad, Carla R; Armer, Hannah; Munro, Peter M G; Blundell, Michael P; Charras, Guillaume; Tolar, Pavel; Bouma, Gerben; Thrasher, Adrian J

2016-05-01

The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability. © The Author(s).

The Human Natural Killer Cell Immune Synapse

NASA Astrophysics Data System (ADS)

Davis, Daniel M.; Chiu, Isaac; Fassett, Marlys; Cohen, George B.; Mandelboim, Ofer; Strominger, Jack L.

1999-12-01

Inhibitory killer Ig-like receptors (KIR) at the surface of natural killer (NK) cells induced clustering of HLA-C at the contacting surface of target cells. In this manner, inhibitory immune synapses were formed as human NK cells surveyed target cells. At target/NK cell synapses, HLA-C/KIR distributed into rings around central patches of intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, the opposite orientation to mature murine T cell-activating synapses. This organization of protein was stable for at least 20 min. Cells could support multiple synapses simultaneously, and clusters of HLA-C moved as NK cells crawled over target cells. Clustering required a divalent metal cation, explaining how metal chelators inhibit KIR function. Surprisingly, however, formation of inhibitory synapses was unaffected by ATP depletion and the cytoskeletal inhibitors, colchicine and cytochalsins B and D. Clearly, supramolecular organization within plasma membranes is critical for NK cell immunosurveillance.

Changes in the serotonergic system and in brain-derived neurotrophic factor distribution in the main olfactory bulb of pcd mice before and after mitral cell loss.

PubMed

Gómez, C; Curto, G G; Baltanás, F C; Valero, J; O'Shea, E; Colado, M I; Díaz, D; Weruaga, E; Alonso, J R

2012-01-10

The serotonergic centrifugal system innervating the main olfactory bulb (MOB) plays a key role in the modulation of olfactory processing. We have previously demonstrated that this system suffers adaptive changes under conditions of a lack of olfactory input. The present work examines the response of this centrifugal system after mitral cell loss in the Purkinje cell degeneration (pcd) mutant mice. The distribution and density of serotonergic centrifugal axons were studied in the MOB of control and pcd mice, both before and after the loss of mitral cells, using serotonin (5-HT) and 5-HT transporter immunohistochemistry. Studies of the amount of 5-HT and its metabolite, 5-hydroxyindole acetic acid (5-HIAA), were performed by means of high-performance liquid chromatography (HPLC), and the relative amounts of brain-derived neurotrophin factor, BDNF, and its major receptor, tropomyosin-related kinase B (TrkB), were measured by Western blot. Our study revealed that the serotonergic system develops adaptive changes after, but not before, mitral cell loss. The lack of the main bulbar projection cells causes a decrease in the serotonergic input received by the MOB, whereas the number of serotonergic cells in the raphe nuclei remains constant. In addition, one of the molecules directly involved in serotonergic sprouting, the neurotrophin BDNF and its main receptor TrkB, underwent alterations in the MOBs of the pcd animals even before the loss of mitral cells. These data indicate that serotonergic function in the MOB is closely related to olfactory activity and that mitral cell loss induces serotonergic plastic responses. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Anergic CD4+ T cells form mature immunological synapses with enhanced accumulation of c-Cbl and Cbl-b1

PubMed Central

Doherty, Melissa; Osborne, Douglas G.; Browning, Diana L.; Parker, David C.; Wetzel, Scott A.

2010-01-01

CD4+ T cell recognition of MHC:peptide complexes in the context of a costimulatory signal results in the large-scale redistribution of molecules at the T-APC interface to form the immunological synapse. The immunological synapse is the location of sustained TCR signaling and delivery of a subset of effector functions. T cells activated in the absence of costimulation are rendered anergic and are hyporesponsive when presented with antigen in the presence of optimal costimulation. Several previous studies have looked at aspects of immunological synapses formed by anergic T cells, but it remains unclear whether there are differences in the formation or composition of anergic immunological synapses. In this study we anergized primary murine CD4+ T cells by incubation of costimulation-deficient, transfected fibroblast APC. Using a combination of TCR, MHC:peptide, and ICAM-1 staining, we found that anergic T cells make mature immunological synapses with characteristic cSMAC and pSMAC domains that were indistinguishable from control synapses. There were small increases in total phosphotyrosine at the anergic synapse along with significant decreases in phosphorylated ERK 1/2 accumulation. Most striking, there was specific accumulation of c-Cbl and Cbl-b to the anergic synapses. Cbl-b, previously shown to be essential in anergy induction, was found in both the pSMAC and the cSMAC of the anergic synapse. This Cbl-b (and c-Cbl) accumulation at the anergic synapse may play an important role in anergy maintenance and/or induction. PMID:20207996

Synapse maintenance and restoration in the retina by NGL2

PubMed Central

Zhao, Lei

2018-01-01

Synaptic cell adhesion molecules (CAMs) promote synapse formation in the developing nervous system. To what extent they maintain and can restore connections in the mature nervous system is unknown. Furthermore, how synaptic CAMs affect the growth of synapse-bearing neurites is unclear. Here, we use adeno-associated viruses (AAVs) to delete, re-, and overexpress the synaptic CAM NGL2 in individual retinal horizontal cells. When we removed NGL2 from horizontal cells, their axons overgrew and formed fewer synapses, irrespective of whether Ngl2 was deleted during development or in mature circuits. When we re-expressed NGL2 in knockout mice, horizontal cell axon territories and synapse numbers were restored, even if AAVs were injected after phenotypes had developed. Finally, overexpression of NGL2 in wild-type horizontal cells elevated synapse numbers above normal levels. Thus, NGL2 promotes the formation, maintenance, and restoration of synapses in the developing and mature retina, and restricts axon growth throughout life. PMID:29553369

Pharmacological Analysis of Ionotropic Glutamate Receptor Function in Neuronal Circuits of the Zebrafish Olfactory Bulb

PubMed Central

Tabor, Rico; Friedrich, Rainer W.

2008-01-01

Although synaptic functions of ionotropic glutamate receptors in the olfactory bulb have been studied in vitro, their roles in pattern processing in the intact system remain controversial. We therefore examined the functions of ionotropic glutamate receptors during odor processing in the intact olfactory bulb of zebrafish using pharmacological manipulations. Odor responses of mitral cells and interneurons were recorded by electrophysiology and 2-photon Ca2+ imaging. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of mitral cells. The blockade of AMPA/kainate receptors alone, in contrast, increased the mean response of mitral cells and decreased the mean response of interneurons. The blockade of NMDA receptors caused little or no change in the mean responses of mitral cells and interneurons. However, antagonists of both receptor types had diverse effects on the magnitude and time course of individual mitral cell and interneuron responses and, thus, changed spatio-temporal activity patterns across neuronal populations. Oscillatory synchronization was abolished or reduced by AMPA/kainate and NMDA receptor antagonists, respectively. These results indicate that (1) interneuron responses depend mainly on AMPA/kainate receptor input during an odor response, (2) interactions among mitral cells and interneurons regulate the total olfactory bulb output activity, (3) AMPA/kainate receptors participate in the synchronization of odor-dependent neuronal ensembles, and (4) ionotropic glutamate receptor-containing synaptic circuits shape odor-specific patterns of olfactory bulb output activity. These mechanisms are likely to be important for the processing of odor-encoding activity patterns in the olfactory bulb. PMID:18183297

Synaptic noise is an information bottleneck in the inner retina during dynamic visual stimulation

PubMed Central

Freed, Michael A; Liang, Zhiyin

2014-01-01

In daylight, noise generated by cones determines the fidelity with which visual signals are initially encoded. Subsequent stages of visual processing require synapses from bipolar cells to ganglion cells, but whether these synapses generate a significant amount of noise was unknown. To characterize noise generated by these synapses, we recorded excitatory postsynaptic currents from mammalian retinal ganglion cells and subjected them to a computational noise analysis. The release of transmitter quanta at bipolar cell synapses contributed substantially to the noise variance found in the ganglion cell, causing a significant loss of fidelity from bipolar cell array to postsynaptic ganglion cell. Virtually all the remaining noise variance originated in the presynaptic circuit. Circuit noise had a frequency content similar to noise shared by ganglion cells but a very different frequency content from noise from bipolar cell synapses, indicating that these synapses constitute a source of independent noise not shared by ganglion cells. These findings contribute a picture of daylight retinal circuits where noise from cones and noise generated by synaptic transmission of cone signals significantly limit visual fidelity. PMID:24297850

How and why does the immunological synapse form? Physical chemistry meets cell biology.

PubMed

Chakraborty, Arup K

2002-03-05

During T lymphocyte (T cell) recognition of an antigen, a highly organized and specific pattern of membrane proteins forms in the junction between the T cell and the antigen-presenting cell (APC). This specialized cell-cell junction is called the immunological synapse. It is several micrometers large and forms over many minutes. A plethora of experiments are being performed to study the mechanisms that underlie synapse formation and the way in which information transfer occurs across the synapse. The wealth of experimental data that is beginning to emerge must be understood within a mechanistic framework if it is to prove useful in developing modalities to control the immune response. Quantitative models can complement experiments in the quest for such a mechanistic understanding by suggesting experimentally testable hypotheses. Here, a quantitative synapse assembly model is described. The model uses concepts developed in physical chemistry and cell biology and is able to predict the spatiotemporal evolution of cell shape and receptor protein patterns observed during synapse formation. Attention is directed to how the juxtaposition of model predictions and experimental data has led to intriguing hypotheses regarding the role of null and self peptides during synapse assembly, as well as correlations between T cell effector functions and the robustness of synapse assembly. We remark on some ways in which synergistic experiments and modeling studies can improve current models, and we take steps toward a better understanding of information transfer across the T cell-APC junction.

Transfer characteristics of the hair cell's afferent synapse

NASA Astrophysics Data System (ADS)

Keen, Erica C.; Hudspeth, A. J.

2006-04-01

The sense of hearing depends on fast, finely graded neurotransmission at the ribbon synapses connecting hair cells to afferent nerve fibers. The processing that occurs at this first chemical synapse in the auditory pathway determines the quality and extent of the information conveyed to the central nervous system. Knowledge of the synapse's input-output function is therefore essential for understanding how auditory stimuli are encoded. To investigate the transfer function at the hair cell's synapse, we developed a preparation of the bullfrog's amphibian papilla. In the portion of this receptor organ representing stimuli of 400-800 Hz, each afferent nerve fiber forms several synaptic terminals onto one to three hair cells. By performing simultaneous voltage-clamp recordings from presynaptic hair cells and postsynaptic afferent fibers, we established that the rate of evoked vesicle release, as determined from the average postsynaptic current, depends linearly on the amplitude of the presynaptic Ca2+ current. This result implies that, for receptor potentials in the physiological range, the hair cell's synapse transmits information with high fidelity. auditory system | exocytosis | glutamate | ribbon synapse | synaptic vesicle

Structure and Function of the Hair Cell Ribbon Synapse

PubMed Central

Nouvian, R.; Beutner, D.; Parsons, T.D.

2006-01-01

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse — the electron-dense synaptic ribbon or synaptic body — has been recognized for decades, dissection of the synapse’s molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years. PMID:16773499

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

PubMed Central

Barreira da Silva, Rosa; Graf, Claudine

2011-01-01

Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)–cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells. PMID:21917751

Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes

PubMed Central

McMahon, Samuel A.; Díaz, Elva

2011-01-01

Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of pre- and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses. PMID:21242087

The mechanobiology of mitral valve function, degeneration, and repair

PubMed Central

Richards, Jennifer M.; Farrar, Emily J.; Kornreich, Bruce G.; Moïse, N. Sydney; Butcher, Jonathan T.

2013-01-01

In degenerative valve disease, the highly organized mitral valve leaflet matrix stratification is progressively destroyed and replaced with proteoglycan rich, mechanically inadequate tissue. This is driven by the actions of originally quiescent valve interstitial cells that become active contractile and migratory myofibroblasts. While treatment for myxomatous mitral valve disease in humans ranges from repair to total replacement, therapies in dogs focus on treating the consequences of the resulting mitral regurgitation. The fundamental gap in our understanding is how the resident valve cells respond to altered mechanical signals to drive tissue remodeling. Despite the pathological similarities and high clinical occurrence, surprisingly little mechanistic insight has been gleaned from the dog. This review presents what is known about mitral valve mechanobiology from clinical, in vivo, and in vitro data. There are a number of experimental strategies already available to pursue this significant opportunity, but success requires the collaboration between veterinary clinicians, scientists, and engineers. PMID:22366572

Neuroligin-1 overexpression in newborn granule cells in vivo.

PubMed

Schnell, Eric; Bensen, Aesoon L; Washburn, Eric K; Westbrook, Gary L

2012-01-01

Adult-born dentate granule cells integrate into the hippocampal network, extend neurites and form synapses in otherwise mature tissue. Excitatory and inhibitory inputs innervate these new granule cells in a stereotyped, temporally segregated manner, which presents a unique opportunity to study synapse development in the adult brain. To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1-overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse-inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1-overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons.

The Relationship between Respiration-Related Membrane Potential Slow Oscillations and Discharge Patterns in Mitral/Tufted Cells: What Are the Rules?

PubMed Central

Briffaud, Virginie; Fourcaud-Trocmé, Nicolas; Messaoudi, Belkacem; Buonviso, Nathalie; Amat, Corine

2012-01-01

Background A slow respiration-related rhythm strongly shapes the activity of the olfactory bulb. This rhythm appears as a slow oscillation that is detectable in the membrane potential, the respiration-related spike discharge of the mitral/tufted cells and the bulbar local field potential. Here, we investigated the rules that govern the manifestation of membrane potential slow oscillations (MPSOs) and respiration-related discharge activities under various afferent input conditions and cellular excitability states. Methodology and Principal Findings We recorded the intracellular membrane potential signals in the mitral/tufted cells of freely breathing anesthetized rats. We first demonstrated the existence of multiple types of MPSOs, which were influenced by odor stimulation and discharge activity patterns. Complementary studies using changes in the intracellular excitability state and a computational model of the mitral cell demonstrated that slow oscillations in the mitral/tufted cell membrane potential were also modulated by the intracellular excitability state, whereas the respiration-related spike activity primarily reflected the afferent input. Based on our data regarding MPSOs and spike patterns, we found that cells exhibiting an unsynchronized discharge pattern never exhibited an MPSO. In contrast, cells with a respiration-synchronized discharge pattern always exhibited an MPSO. In addition, we demonstrated that the association between spike patterns and MPSO types appeared complex. Conclusion We propose that both the intracellular excitability state and input strength underlie specific MPSOs, which, in turn, constrain the types of spike patterns exhibited. PMID:22952828

Actin Engine in Immunological Synapse

PubMed Central

Piragyte, Indre

2012-01-01

T cell activation and function require physical contact with antigen presenting cells at a specialized junctional structure known as the immunological synapse. Once formed, the immunological synapse leads to sustained T cell receptor-mediated signalling and stabilized adhesion. High resolution microscopy indeed had a great impact in understanding the function and dynamic structure of immunological synapse. Trends of recent research are now moving towards understanding the mechanical part of immune system, expanding our knowledge in mechanosensitivity, force generation, and biophysics of cell-cell interaction. Actin cytoskeleton plays inevitable role in adaptive immune system, allowing it to bear dynamic and precise characteristics at the same time. The regulation of mechanical engine seems very complicated and overlapping, but it enables cells to be very sensitive to external signals such as surface rigidity. In this review, we focus on actin regulators and how immune cells regulate dynamic actin rearrangement process to drive the formation of immunological synapse. PMID:22916042

Large variability in synaptic N-methyl-D-aspartate receptor density on interneurons and a comparison with pyramidal-cell spines in the rat hippocampus.

PubMed

Nyíri, G; Stephenson, F A; Freund, T F; Somogyi, P

2003-01-01

Pyramidal cells receive input from several types of GABA-releasing interneurons and innervate them reciprocally. Glutamatergic activation of interneurons involves both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) type glutamate receptors expressed in type I synapses, mostly on their dendritic shafts. On average, the synaptic AMPA receptor content is several times higher on interneurons than in the spines of pyramidal cells. To compare the NMDA receptor content of synapses, we used a quantitative postembedding immunogold technique on serial electron microscopic sections, and analysed the synapses on interneuron dendrites and pyramidal cell spines in the CA1 area. Because all NMDA receptors contain the obligatory NR1 subunit, receptor localisation was carried out using antibodies recognising all splice variants of the NR1 subunit. Four populations of synapse were examined: i). on spines of pyramidal cells in stratum (str.) radiatum and str. oriens; ii). on parvalbumin-positive interneuronal dendritic shafts in str. radiatum; iii). on randomly found dendritic shafts in str. oriens and iv). on somatostatin-positive interneuronal dendritic shafts and somata in str. oriens. On average, the size of the synapses on spines was about half of those on interneurons. The four populations of synapse significantly differed in labelling for the NR1 subunit. The median density of NR1 subunit labelling was highest on pyramidal cell spines. It was lowest in the synapses on parvalbumin-positive dendrites in str. radiatum, where more than half of these synapses were immunonegative. In str. oriens, synapses on interneurons had a high variability of receptor content; some dendrites were similar to those in str. radiatum, including the proximal synapses of somatostatin-positive cells, whereas others had immunoreactivity for the NR1 subunit similar to or higher than synapses on pyramidal cell spines. These results show that synaptic NMDA receptor density differs between pyramidal cells and interneurons. Some interneurons may have a high NMDA receptor content, whereas others, like some parvalbumin-expressing cells, a particularly low synaptic NMDA receptor content. Consequently, fast glutamatergic activation of interneurons is expected to show cell type-specific time course and state-dependent dynamics.

Immunocytochemical analysis of syntaxin-1 in rat circumvallate taste buds.

PubMed

Yang, Ruibiao; Ma, Huazhi; Thomas, Stacey M; Kinnamon, John C

2007-06-20

Mammalian buds contain a variety of morphological taste cell types, but the type III taste cell is the only cell type that has synapses onto nerve processes. We hypothesize that taste cell synapses utilize the SNARE protein machinery syntaxin, SNAP-25, and synaptobrevin, as is used by synapses in the central nervous system (CNS) for Ca2+-dependent exocytosis. Previous studies have shown that taste cells with synapses display SNAP-25- and synaptobrevin-2-like immunoreactivity (LIR) (Yang et al. [2000a] J Comp Neurol 424:205-215, [2004] J Comp Neurol 471:59-71). In the present study we investigated the presynaptic membrane protein, syntaxin-1, in circumvallate taste buds of the rat. Our results indicate that diffuse cytoplasmic and punctate syntaxin-1-LIR are present in different subsets of taste cells. Diffuse, cytoplasmic syntaxin-1-LIR is present in type III cells while punctate syntaxin-1-LIR is present in type II cells. The punctate syntaxin-1-LIR is believed to be associated with Golgi bodies. All of the synapses associated with syntaxin-1-LIR taste cells are from type III cells onto nerve processes. These results support the proposition that taste cell synapses use classical SNARE machinery such as syntaxin-1 for neurotransmitter release in rat circumvallate taste buds. (c) 2007 Wiley-Liss, Inc.

Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses.

PubMed

Soares, Helena; Lasserre, Rémi; Alcover, Andrés

2013-11-01

Immunological synapses are specialized cell-cell contacts formed between T lymphocytes and antigen-presenting cells. They are induced upon antigen recognition and are crucial for T-cell activation and effector functions. The generation and function of immunological synapses depend on an active T-cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T-cell responses. We discuss here our view on how T-cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T-cell activation. We also discuss how the human immunodeficiency virus (HIV-1) hijacks some of these processes impairing immunological synapse generation and function. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pathology of myxomatous mitral valve disease in the dog.

PubMed

Fox, Philip R

2012-03-01

Mitral valve competence requires complex interplay between structures that comprise the mitral apparatus - the mitral annulus, mitral valve leaflets, chordae tendineae, papillary muscles, and left atrial and left ventricular myocardium. Myxomatous mitral valve degeneration is prevalent in the canine, and most adult dogs develop some degree of mitral valve disease as they age, highlighting the apparent vulnerability of canine heart valves to injury. Myxomatous valvular remodeling is associated with characteristic histopathologic features. Changes include expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of myxomatous valve disease and in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure. Future studies are necessary to identify clinical-pathologic correlates that track disease severity and progression, detect valve dysfunction, and facilitate risk stratification. It remains unresolved whether, or to what extent, the pathobiology of myxomatous mitral valve degeneration is the same between breeds of dogs, between canines and humans, and how these features are related to aging and genetics. Copyright © 2012 Elsevier B.V. All rights reserved.

Transmission, Development, and Plasticity of Synapses

PubMed Central

Harris, Kathryn P.

2015-01-01

Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre- and postsynaptic cells communicate to regulate plasticity in response to activity. PMID:26447126

Involvement of intracellular Zn2+ signaling in LTP at perforant pathway-CA1 pyramidal cell synapse.

PubMed

Tamano, Haruna; Nishio, Ryusuke; Takeda, Atsushi

2017-07-01

Physiological significance of synaptic Zn 2+ signaling was examined at perforant pathway-CA1 pyramidal cell synapses. In vivo long-term potentiation (LTP) at perforant pathway-CA1 pyramidal cell synapses was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. Perforant pathway LTP was not attenuated under perfusion with CaEDTA (10 mM), an extracellular Zn 2+ chelator, but attenuated under perfusion with ZnAF-2DA (50 μM), an intracellular Zn 2+ chelator, suggesting that intracellular Zn 2+ signaling is required for perforant pathway LTP. Even in rat brain slices bathed in CaEDTA in ACSF, intracellular Zn 2+ level, which was measured with intracellular ZnAF-2, was increased in the stratum lacunosum-moleculare where perforant pathway-CA1 pyramidal cell synapses were contained after tetanic stimulation. These results suggest that intracellular Zn 2+ signaling, which originates in internal stores/proteins, is involved in LTP at perforant pathway-CA1 pyramidal cell synapses. Because the influx of extracellular Zn 2+ , which originates in presynaptic Zn 2+ release, is involved in LTP at Schaffer collateral-CA1 pyramidal cell synapses, synapse-dependent Zn 2+ dynamics may be involved in plasticity of postsynaptic CA1 pyramidal cells. © 2017 Wiley Periodicals, Inc.

The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells.

PubMed

Rubio, María E; Matsui, Ko; Fukazawa, Yugo; Kamasawa, Naomi; Harada, Harumi; Itakura, Makoto; Molnár, Elek; Abe, Manabu; Sakimura, Kenji; Shigemoto, Ryuichi

2017-11-01

The neurotransmitter receptor subtype, number, density, and distribution relative to the location of transmitter release sites are key determinants of signal transmission. AMPA-type ionotropic glutamate receptors (AMPARs) containing GluA3 and GluA4 subunits are prominently expressed in subsets of neurons capable of firing action potentials at high frequencies, such as auditory relay neurons. The auditory nerve (AN) forms glutamatergic synapses on two types of relay neurons, bushy cells (BCs) and fusiform cells (FCs) of the cochlear nucleus. AN-BC and AN-FC synapses have distinct kinetics; thus, we investigated whether the number, density, and localization of GluA3 and GluA4 subunits in these synapses are differentially organized using quantitative freeze-fracture replica immunogold labeling. We identify a positive correlation between the number of AMPARs and the size of AN-BC and AN-FC synapses. Both types of AN synapses have similar numbers of AMPARs; however, the AN-BC have a higher density of AMPARs than AN-FC synapses, because the AN-BC synapses are smaller. A higher number and density of GluA3 subunits are observed at AN-BC synapses, whereas a higher number and density of GluA4 subunits are observed at AN-FC synapses. The intrasynaptic distribution of immunogold labeling revealed that AMPAR subunits, particularly GluA3, are concentrated at the center of the AN-BC synapses. The central distribution of AMPARs is absent in GluA3-knockout mice, and gold particles are evenly distributed along the postsynaptic density. GluA4 gold labeling was homogenously distributed along both synapse types. Thus, GluA3 and GluA4 subunits are distributed at AN synapses in a target-cell-dependent manner.

The cytotoxic T lymphocyte immune synapse at a glance.

PubMed

Dieckmann, Nele M G; Frazer, Gordon L; Asano, Yukako; Stinchcombe, Jane C; Griffiths, Gillian M

2016-08-01

The immune synapse provides an important structure for communication with immune cells. Studies on immune synapses formed by cytotoxic T lymphocytes (CTLs) highlight the dynamic changes and specialised mechanisms required to facilitate focal signalling and polarised secretion in immune cells. In this Cell Science at a Glance article and the accompanying poster, we illustrate the different steps that reveal the specialised mechanisms used to focus secretion at the CTL immune synapse and allow CTLs to be such efficient and precise serial killers. © 2016. Published by The Company of Biologists Ltd.

Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability

PubMed Central

Santos, Luís C; Blair, David A; Kumari, Sudha; Cammer, Michael; Iskratsch, Thomas; Herbin, Olivier; Alexandropoulos, Konstantina

2016-01-01

The immunological synapse formed between a T‐cell and an antigen‐presenting cell is important for cell–cell communication during T‐cell‐mediated immune responses. Immunological synapse formation begins with stimulation of the T‐cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization‐dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte‐specific Crk‐associated substrate (Cas‐L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas‐L is phosphorylated at TCR microclusters in an actin polymerization‐dependent fashion. Furthermore, Cas‐L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside–out integrin activation, and actomyosin contraction. We propose a new role for Cas‐L in T‐cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin‐dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T‐cell‐mediated immune responses. PMID:27359298

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse.

PubMed

Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W; Tsai, Jones; Gordo, Susana; Wucherpfennig, Kai W; Kam, Lance C; Stokes, David L; Dustin, Michael L

2014-03-06

The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.

Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse

NASA Astrophysics Data System (ADS)

Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W.; Tsai, Jones; Gordo, Susana; Wucherpfennig, Kai W.; Kam, Lance C.; Stokes, David L.; Dustin, Michael L.

2014-03-01

The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.

A biophysical signature of network affiliation and sensory processing in mitral cells

PubMed Central

Angelo, Kamilla; Rancz, Ede A.; Pimentel, Diogo; Hundahl, Christian; Hannibal, Jens; Fleischmann, Alexander; Pichler, Bruno; Margrie, Troy W.

2012-01-01

One defining characteristic of the mammalian brain is its neuronal diversity1. For a given region, substructure or layer and even cell type2, variability in neuronal morphology and connectivity2-5 persists. While it is well established that such cellular properties vary considerably according to neuronal type, the significant biophysical diversity of neurons of the same morphological class is typically averaged out and ignored. Here we show that the amplitude of hyperpolarization-evoked membrane potential sag recorded in olfactory bulb mitral cells is an emergent, homotypic property of local networks and sensory information processing. Simultaneous whole-cell recordings from pairs of cells reveal that the amount of hyperpolarization-evoked sag potential and current6 is stereotypic for mitral cells belonging to the same glomerular circuit. This is corroborated by a mosaic, glomerulus-based pattern of expression of the HCN2 subunit of the hyperpolarization-activated current (Ih) channel. Furthermore, inter-glomerular differences in both membrane potential sag and HCN2 protein are diminished when sensory input to glomeruli is genetically and globally altered so only one type of odorant receptor is universally expressed7. We therefore suggest that population diversity in the intrinsic profile of mitral cells reflect functional adaptations of distinct local circuits dedicated to processing subtly different odor-related information. PMID:22820253

T cells' immunological synapses induce polarization of brain astrocytes in vivo and in vitro: a novel astrocyte response mechanism to cellular injury.

PubMed

Barcia, Carlos; Sanderson, Nicholas S R; Barrett, Robert J; Wawrowsky, Kolja; Kroeger, Kurt M; Puntel, Mariana; Liu, Chunyan; Castro, Maria G; Lowenstein, Pedro R

2008-08-20

Astrocytes usually respond to trauma, stroke, or neurodegeneration by undergoing cellular hypertrophy, yet, their response to a specific immune attack by T cells is poorly understood. Effector T cells establish specific contacts with target cells, known as immunological synapses, during clearance of virally infected cells from the brain. Immunological synapses mediate intercellular communication between T cells and target cells, both in vitro and in vivo. How target virally infected astrocytes respond to the formation of immunological synapses established by effector T cells is unknown. Herein we demonstrate that, as a consequence of T cell attack, infected astrocytes undergo dramatic morphological changes. From normally multipolar cells, they become unipolar, extending a major protrusion towards the immunological synapse formed by the effector T cells, and withdrawing most of their finer processes. Thus, target astrocytes become polarized towards the contacting T cells. The MTOC, the organizer of cell polarity, is localized to the base of the protrusion, and Golgi stacks are distributed throughout the protrusion, reaching distally towards the immunological synapse. Thus, rather than causing astrocyte hypertrophy, antiviral T cells cause a major structural reorganization of target virally infected astrocytes. Astrocyte polarization, as opposed to hypertrophy, in response to T cell attack may be due to T cells providing a very focused attack, and thus, astrocytes responding in a polarized manner. A similar polarization of Golgi stacks towards contacting T cells was also detected using an in vitro allogeneic model. Thus, different T cells are able to induce polarization of target astrocytes. Polarization of target astrocytes in response to immunological synapses may play an important role in regulating the outcome of the response of astrocytes to attacking effector T cells, whether during antiviral (e.g. infected during HIV, HTLV-1, HSV-1 or LCMV infection), anti-transplant, autoimmune, or anti-tumor immune responses in vivo and in vitro.

Mitral valve disease—morphology and mechanisms

PubMed Central

Levine, Robert A.; Hagége, Albert A.; Judge, Daniel P.; Padala, Muralidhar; Dal-Bianco, Jacob P.; Aikawa, Elena; Beaudoin, Jonathan; Bischoff, Joyce; Bouatia-Naji, Nabila; Bruneval, Patrick; Butcher, Jonathan T.; Carpentier, Alain; Chaput, Miguel; Chester, Adrian H.; Clusel, Catherine; Delling, Francesca N.; Dietz, Harry C.; Dina, Christian; Durst, Ronen; Fernandez-Friera, Leticia; Handschumacher, Mark D.; Jensen, Morten O.; Jeunemaitre, Xavier P.; Le Marec, Hervé; Le Tourneau, Thierry; Markwald, Roger R.; Mérot, Jean; Messas, Emmanuel; Milan, David P.; Neri, Tui; Norris, Russell A.; Peal, David; Perrocheau, Maelle; Probst, Vincent; Pucéat, Michael; Rosenthal, Nadia; Solis, Jorge; Schott, Jean-Jacques; Schwammenthal, Ehud; Slaugenhaupt, Susan A.; Song, Jae-Kwan; Yacoub, Magdi H.

2016-01-01

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease. PMID:26483167

The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling T-cell receptors to the immune synapse

PubMed Central

Finetti, Francesca; Patrussi, Laura; Galgano, Donatella; Cassioli, Chiara; Perinetti, Giuseppe; Pazour, Gregory J.; Baldari, Cosima T.

2015-01-01

ABSTRACT IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11+ endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR+ endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the final docking or fusion step. This could be accounted for by the inability of the vesicular (v)-SNARE VAMP-3 to cluster at the immune synapse in the absence of functional Rab8, which is responsible for its recruitment. Of note, and similar to in T-cells, VAMP-3 interacts with Rab8 at the base of the cilium in NIH-3T3 cells, where it regulates ciliary growth and targeting of the protein smoothened. The results identify Rab8 as a new player in vesicular traffic to the immune synapse and provide insight into the pathways co-opted by different cell types for immune synapse assembly and ciliogenesis. PMID:26034069

The role of synaptotagmin I C2A calcium-binding domain in synaptic vesicle clustering during synapse formation

PubMed Central

Gardzinski, Peter; Lee, David W K; Fei, Guang-He; Hui, Kwokyin; Huang, Guan J; Sun, Hong-Shuo; Feng, Zhong-Ping

2007-01-01

Synaptic vesicles aggregate at the presynaptic terminal during synapse formation via mechanisms that are poorly understood. Here we have investigated the role of the putative calcium sensor synaptotagmin I in vesicle aggregation during the formation of soma–soma synapses between identified partner cells using a simple in vitro synapse model in the mollusc Lymnaea stagnalis. Immunocytochemistry, optical imaging and electrophysiological recording techniques were used to monitor synapse formation and vesicle localization. Within 6 h, contact between appropriate synaptic partner cells up-regulated global synaptotagmin I expression, and induced a localized aggregation of synaptotagmin I at the contact site. Cell contacts between non-synaptic partner cells did not affect synaptotagmin I expression. Application of an human immunodeficiency virus type-1 transactivator (HIV-1 TAT)-tagged peptide corresponding to loop 3 of the synaptotagmin I C2A domain prevented synaptic vesicle aggregation and synapse formation. By contrast, a TAT-tagged peptide containing the calcium-binding motif of the C2B domain did not affect synaptic vesicle aggregation or synapse formation. Calcium imaging with Fura-2 demonstrated that TAT–C2 peptides did not alter either basal or evoked intracellular calcium levels. These results demonstrate that contact with an appropriate target cell is necessary to initiate synaptic vesicle aggregation during nascent synapse formation and that the initial aggregation of synaptic vesicles is dependent on loop 3 of the C2A domain of synaptotagmin I. PMID:17317745

Hair cell ribbon synapses

PubMed Central

Brandt, Andreas; Lysakowski, Anna

2010-01-01

Hearing and balance rely on the faithful synaptic coding of mechanical input by the auditory and vestibular hair cells of the inner ear. Mechanical deflection of their stereocilia causes the opening of mechanosensitive channels, resulting in hair cell depolarization, which controls the release of glutamate at ribbon-type synapses. Hair cells have a compact shape with strong polarity. Mechanoelectrical transduction and active membrane turnover associated with stereociliar renewal dominate the apical compartment. Transmitter release occurs at several active zones along the basolateral membrane. The astonishing capability of the hair cell ribbon synapse for temporally precise and reliable sensory coding has been the subject of intense investigation over the past few years. This research has been facilitated by the excellent experimental accessibility of the hair cell. For the same reason, the hair cell serves as an important model for studying presynaptic Ca2+ signaling and stimulus-secretion coupling. In addition to common principles, hair cell synapses differ in their anatomical and functional properties among species, among the auditory and vestibular organs, and among hair cell positions within the organ. Here, we briefly review synaptic morphology and connectivity and then focus on stimulus-secretion coupling at hair cell synapses. PMID:16944206

The immunological synapse

PubMed Central

Dustin, Michael L.

2015-01-01

The molecular interactions underlying regulation of the immune response take place in a nano-scale gap between T cells and antigen presenting cells, termed the immunological synapse. If these interactions are regulated appropriately, the host is defended against a wide range of pathogens and deranged host cells. If these interactions are dis-regulated, the host is susceptible to pathogens or tumor escape at one extreme and autoimmunity at the other. Treatments targeting the synapse have helped to establish immunotherapy as a mainstream element in cancer treatment. This Masters primer will cover the basics of the immunological synapse and some of the applications to tumor immunology. PMID:25367977

Voltage-Gated Calcium Influx Modifies Cholinergic Inhibition of Inner Hair Cells in the Immature Rat Cochlea.

PubMed

Zachary, Stephen; Nowak, Nathaniel; Vyas, Pankhuri; Bonanni, Luke; Fuchs, Paul Albert

2018-06-20

Until postnatal day (P) 12, inner hair cells of the rat cochlea are invested with both afferent and efferent synaptic connections. With the onset of hearing at P12, the efferent synapses disappear, and afferent (ribbon) synapses operate with greater efficiency. This change coincides with increased expression of voltage-gated potassium channels, the loss of calcium-dependent electrogenesis, and the onset of graded receptor potentials driven by sound. The transient efferent synapses include near-membrane postsynaptic cisterns thought to regulate calcium influx through the hair cell's α9-containing and α10-containing nicotinic acetylcholine receptors. This influx activates small-conductance Ca 2+ -activated K + (SK) channels. Serial-section electron microscopy of inner hair cells from two 9-d-old (male) rat pups revealed many postsynaptic efferent cisterns and presynaptic afferent ribbons whose average minimal separation in five cells ranged from 1.1 to 1.7 μm. Efferent synaptic function was studied in rat pups (age, 7-9 d) of either sex. The duration of these SK channel-mediated IPSCs was increased by enhanced calcium influx through L-type voltage-gated channels, combined with ryanodine-sensitive release from internal stores-presumably the near-membrane postsynaptic cistern. These data support the possibility that inner hair cell calcium electrogenesis modulates the efficacy of efferent inhibition during the maturation of inner hair cell synapses. SIGNIFICANCE STATEMENT Strict calcium buffering is essential for cellular function. This problem is especially acute for compact hair cells where increasing cytoplasmic calcium promotes the opposing functions of closely adjoining afferent and efferent synapses. The near-membrane postsynaptic cistern at efferent synapses segregates synaptic calcium signals by acting as a dynamic calcium store. The hair cell serves as an informative model for synapses with postsynaptic cisterns (C synapses) found in central neurons. Copyright © 2018 the authors 0270-6474/18/385677-11$15.00/0.

Distinct lateral inhibitory circuits drive parallel processing of sensory information in the mammalian olfactory bulb

PubMed Central

Geramita, Matthew A; Burton, Shawn D; Urban, Nathan N

2016-01-01

Splitting sensory information into parallel pathways is a common strategy in sensory systems. Yet, how circuits in these parallel pathways are composed to maintain or even enhance the encoding of specific stimulus features is poorly understood. Here, we have investigated the parallel pathways formed by mitral and tufted cells of the olfactory system in mice and characterized the emergence of feature selectivity in these cell types via distinct lateral inhibitory circuits. We find differences in activity-dependent lateral inhibition between mitral and tufted cells that likely reflect newly described differences in the activation of deep and superficial granule cells. Simulations show that these circuit-level differences allow mitral and tufted cells to best discriminate odors in separate concentration ranges, indicating that segregating information about different ranges of stimulus intensity may be an important function of these parallel sensory pathways. DOI: http://dx.doi.org/10.7554/eLife.16039.001 PMID:27351103

Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation

PubMed Central

Fritzsche, Marco; Fernandes, Ricardo A.; Chang, Veronica T.; Colin-York, Huw; Clausen, Mathias P.; Felce, James H.; Galiani, Silvia; Erlenkämper, Christoph; Santos, Ana M.; Heddleston, John M.; Pedroza-Pacheco, Isabela; Waithe, Dominic; de la Serna, Jorge Bernardino; Lagerholm, B. Christoffer; Liu, Tsung-li; Chew, Teng-Leong; Betzig, Eric; Davis, Simon J.; Eggeling, Christian

2017-01-01

T cell activation and especially trafficking of T cell receptor microclusters during immunological synapse formation are widely thought to rely on cytoskeletal remodeling. However, important details on the involvement of actin in the latter transport processes are missing. Using a suite of advanced optical microscopes to analyze resting and activated T cells, we show that, following contact formation with activating surfaces, these cells sequentially rearrange their cortical actin across the entire cell, creating a previously unreported ramifying actin network above the immunological synapse. This network shows all the characteristics of an inward-growing transportation network and its dynamics correlating with T cell receptor rearrangements. This actin reorganization is accompanied by an increase in the nanoscale actin meshwork size and the dynamic adjustment of the turnover times and filament lengths of two differently sized filamentous actin populations, wherein formin-mediated long actin filaments support a very flat and stiff contact at the immunological synapse interface. The initiation of immunological synapse formation, as highlighted by calcium release, requires markedly little contact with activating surfaces and no cytoskeletal rearrangements. Our work suggests that incipient signaling in T cells initiates global cytoskeletal rearrangements across the whole cell, including a stiffening process for possibly mechanically supporting contact formation at the immunological synapse interface as well as a central ramified transportation network apparently directed at the consolidation of the contact and the delivery of effector functions. PMID:28691087

Ribbon Synaptic Plasticity in Gravity Sensors of Rats Flown on Neurolab

NASA Technical Reports Server (NTRS)

Ross, Muriel D.; Varelas, Joseph

2003-01-01

Previous spaceflight experiments (Space Life Sciences-1 and -2 (SLS-1 and SLS-2)) first demonstrated the extraordinary ability of gravity sensor hair cells to change the number, kind, and distribution of connections (synapses) they make to other cells while in weightlessness. The number of synapses in hair cells in one part of the inner ear (the utricle) was markedly elevated on flight day 13 (FD13) of SLS-2. Unanswered questions, however, were whether these increases in synapses occur rapidly and whether they remain stable in weightlessness. The answers have implications for long-duration human space travel. If gravity sensors can adapt quickly, crews may be able to move easily between different gravity levels, since the sensors will adapt rapidly to weightlessness on the spacecraft and then back to Earth's gravity when the mission ends. This ability to adapt is also important for recovery from balance disorders. To further our understanding of this adaptive potential (a property called neuronal synaptic plasticity), the present Neurolab research was undertaken. Our experiment examined whether: (a) increases in synapses would remain stable throughout the flight, (b) changes in the number of synapses were uniform across different portions of the gravity sensors (the utricle and saccule), and (c) synaptic changes were similar for the different types of hair cells (Type I and Type II). Utricular and saccular maculae (the gravity-sensing portions of the inner ear) were collected in flight from rats on FD2 and FD14. Samples were also collected from control rats on the ground. Tissues were prepared for ultrastructural study. Hair cells and their ribbon synapses were examined in a transmission electron microscope. Synapses were counted in all hair cells in 50 consecutive sections that crossed the striolar zone. Results indicate that utricular hair cell synapses initially increased significantly in number in both types of hair cells by FD2. Counts declined by FD14, but the mean number of synapses in utricular Type II cells remained significantly higher than in the ground control rats. For saccular samples, synaptic number in Type I and Type II cells declined on FD2, but returned to near-baseline values by FD14. These findings indicate that: (a) synaptic plasticity occurs rapidly in weightlessness, and (b) synaptic changes are not identical for the two types of hair cells or for the two maculae.

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

PubMed Central

Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

2014-01-01

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses.

PubMed

Carta, Mario; Srikumar, Bettadapura N; Gorlewicz, Adam; Rebola, Nelson; Mulle, Christophe

2018-02-15

CA3 pyramidal cells display input-specific differences in the subunit composition of synaptic NMDA receptors (NMDARs). Although at low density, GluN2B contributes significantly to NMDAR-mediated EPSCs at mossy fibre synapses. Long-term potentiation (LTP) of NMDARs triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. GluN2B subunits are essential for the expression of LTP of NMDARs at mossy fibre synapses. Single neurons express NMDA receptors (NMDARs) with distinct subunit composition and biophysical properties that can be segregated in an input-specific manner. The dynamic control of the heterogeneous distribution of synaptic NMDARs is crucial to control input-dependent synaptic integration and plasticity. In hippocampal CA3 pyramidal cells from mice of both sexes, we found that mossy fibre (MF) synapses display a markedly lower proportion of GluN2B-containing NMDARs than associative/commissural synapses. The mechanism involved in such heterogeneous distribution of GluN2B subunits is not known. Here we show that long-term potentiation (LTP) of NMDARs, which is selectively expressed at MF-CA3 pyramidal cell synapses, triggers a modification in the subunit composition of synaptic NMDARs by insertion of GluN2B. This activity-dependent recruitment of GluN2B at mature MF-CA3 pyramidal cell synapses contrasts with the removal of GluN2B subunits at other glutamatergic synapses during development and in response to activity. Furthermore, although expressed at low levels, GluN2B is necessary for the expression of LTP of NMDARs at MF-CA3 pyramidal cell synapses. Altogether, we reveal a previously unknown activity-dependent regulation and function of GluN2B subunits that may contribute to the heterogeneous plasticity induction rules in CA3 pyramidal cells. © 2017 Centre Nationnal de la Recherche Scientifique. The Journal of Physiology © 2017 The Physiological Society.

Contribution of pheromones processed by the main olfactory system to mate recognition in female mammals

PubMed Central

Baum, Michael J.

2012-01-01

Until recently it was widely believed that the ability of female mammals (with the likely exception of women) to identify and seek out a male breeding partner relied on the detection of non-volatile male pheromones by the female's vomeronasal organ (VNO) and their subsequent processing by a neural circuit that includes the accessory olfactory bulb (AOB), vomeronasal amygdala, and hypothalamus. Emperical data are reviewed in this paper that demonstrate the detection of volatile pheromones by the main olfactory epithelium (MOE) of female mice which, in turn, leads to the activation of a population of glomeruli and abutting mitral cells in the main olfactory bulb (MOB). Anatomical results along with functional neuroanatomical data demonstrate that some of these MOB mitral cells project to the vomeronasal amygdala. These particular MOB mitral cells were selectively activated (i.e., expressed Fos protein) by exposure to male as opposed to female urinary volatiles. A similar selectivity to opposite sex urinary volatiles was also seen in mitral cells of the AOB of female mice. Behavioral data from female mouse, ferret, and human are reviewed that implicate the main olfactory system, in some cases interacting with the accessory olfactory system, in mate recognition. PMID:22679420

Interneuron- and GABAA receptor-specific inhibitory synaptic plasticity in cerebellar Purkinje cells

NASA Astrophysics Data System (ADS)

He, Qionger; Duguid, Ian; Clark, Beverley; Panzanelli, Patrizia; Patel, Bijal; Thomas, Philip; Fritschy, Jean-Marc; Smart, Trevor G.

2015-07-01

Inhibitory synaptic plasticity is important for shaping both neuronal excitability and network activity. Here we investigate the input and GABAA receptor subunit specificity of inhibitory synaptic plasticity by studying cerebellar interneuron-Purkinje cell (PC) synapses. Depolarizing PCs initiated a long-lasting increase in GABA-mediated synaptic currents. By stimulating individual interneurons, this plasticity was observed at somatodendritic basket cell synapses, but not at distal dendritic stellate cell synapses. Basket cell synapses predominantly express β2-subunit-containing GABAA receptors; deletion of the β2-subunit ablates this plasticity, demonstrating its reliance on GABAA receptor subunit composition. The increase in synaptic currents is dependent upon an increase in newly synthesized cell surface synaptic GABAA receptors and is abolished by preventing CaMKII phosphorylation of GABAA receptors. Our results reveal a novel GABAA receptor subunit- and input-specific form of inhibitory synaptic plasticity that regulates the temporal firing pattern of the principal output cells of the cerebellum.

GABAergic circuits control input-spike coupling in the piriform cortex.

PubMed

Luna, Victor M; Schoppa, Nathan E

2008-08-27

Odor coding in mammals is widely believed to involve synchronized gamma frequency (30-70 Hz) oscillations in the first processing structure, the olfactory bulb. How such inputs are read in downstream cortical structures however is not known. Here we used patch-clamp recordings in rat piriform cortex slices to examine cellular mechanisms that shape how the cortex integrates inputs from bulb mitral cells. Electrical stimulation of mitral cell axons in the lateral olfactory tract (LOT) resulted in excitation of pyramidal cells (PCs), which was followed approximately 10 ms later by inhibition that was highly reproducible between trials in its onset time. This inhibition was somatic in origin and appeared to be driven through a feedforward mechanism, wherein GABAergic interneurons were directly excited by mitral cell axons. The precise inhibition affected action potential firing in PCs in two distinct ways. First, by abruptly terminating PC excitation, it limited the PC response to each EPSP to exactly one, precisely timed action potential. In addition, inhibition limited the summation of EPSPs across time, such that PCs fired action potentials in strong preference for synchronized inputs arriving in a time window of <5 ms. Both mechanisms would help ensure that PCs respond faithfully and selectively to mitral cell inputs arriving as a synchronized gamma frequency pattern.

Encoding of luminance and contrast by linear and nonlinear synapses in the retina.

PubMed

Odermatt, Benjamin; Nikolaev, Anton; Lagnado, Leon

2012-02-23

Understanding how neural circuits transmit information is technically challenging because the neural code is contained in the activity of large numbers of neurons and synapses. Here, we use genetically encoded reporters to image synaptic transmission across a population of sensory neurons-bipolar cells in the retina of live zebrafish. We demonstrate that the luminance sensitivities of these synapses varies over 10(4) with a log-normal distribution. About half the synapses made by ON and OFF cells alter their polarity of transmission as a function of luminance to generate a triphasic tuning curve with distinct maxima and minima. These nonlinear synapses signal temporal contrast with greater sensitivity than linear ones. Triphasic tuning curves increase the dynamic range over which bipolar cells signal light and improve the efficiency with which luminance information is transmitted. The most efficient synapses signaled luminance using just 1 synaptic vesicle per second per distinguishable gray level. Copyright © 2012 Elsevier Inc. All rights reserved.

Changes in ribbon synapses and rough endoplasmic reticulum of rat utricular macular hair cells in weightlessness

NASA Technical Reports Server (NTRS)

Ross, M. D.

2000-01-01

This study combined ultrastructural and statistical methods to learn the effects of weightlessness on rat utricular maculae. A principle aim was to determine whether weightlessness chiefly affects ribbon synapses of type II cells, since the cells communicate predominantly with branches of primary vestibular afferent endings. Maculae were microdissected from flight and ground control rat inner ears collected on day 13 of a 14-day spaceflight (F13), landing day (R0) and day 14 postflight (R14) and were prepared for ultrastructural study. Ribbon synapses were counted in hair cells examined in a Zeiss 902 transmission electron microscope. Significance of synaptic mean differences was determined for all hair cells contained within 100 section series, and for a subset of complete hair cells, using SuperANOVA software. The synaptic mean for all type II hair cells of F13 flight rats increased by 100%, and that for complete cells by 200%. Type I cells were less affected, with synaptic mean differences statistically insignificant in complete cells. Synapse deletion began within 8 h upon return to Earth. Additionally, hair cell laminated rough endoplasmic reticulum of flight rats was reversibly disorganized on R0. Results support the thesis that synapses in type II hair cells are uniquely affected by altered gravity. Type II hair cells may be chiefly sensors of gravitational and type I cells of translational linear accelerations.

Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse.

PubMed

Sebe, Joy Y; Cho, Soyoun; Sheets, Lavinia; Rutherford, Mark A; von Gersdorff, Henrique; Raible, David W

2017-06-21

We report functional and structural evidence for GluA2-lacking Ca 2+ -permeable AMPARs (CP-AMPARs) at the mature hair cell ribbon synapse. By using the methodological advantages of three species (of either sex), we demonstrate that CP-AMPARs are present at the hair cell synapse in an evolutionarily conserved manner. Via a combination of in vivo electrophysiological and Ca 2+ imaging approaches in the larval zebrafish, we show that hair cell stimulation leads to robust Ca 2+ influx into afferent terminals. Prolonged application of AMPA caused loss of afferent terminal responsiveness, whereas blocking CP-AMPARs protects terminals from excitotoxic swelling. Immunohistochemical analysis of AMPAR subunits in mature rat cochlea show regions within synapses lacking the GluA2 subunit. Paired recordings from adult bullfrog auditory synapses demonstrate that CP-AMPARs mediate a major component of glutamatergic transmission. Together, our results support the importance of CP-AMPARs in mediating transmission at the hair cell ribbon synapse. Further, excess Ca 2+ entry via CP-AMPARs may underlie afferent terminal damage following excitotoxic challenge, suggesting that limiting Ca 2+ levels in the afferent terminal may protect against cochlear synaptopathy associated with hearing loss. SIGNIFICANCE STATEMENT A single incidence of noise overexposure causes damage at the hair cell synapse that later leads to neurodegeneration and exacerbates age-related hearing loss. A first step toward understanding cochlear neurodegeneration is to identify the cause of initial excitotoxic damage to the postsynaptic neuron. Using a combination of immunohistochemical, electrophysiological, and Ca 2+ imaging approaches in evolutionarily divergent species, we demonstrate that Ca 2+ -permeable AMPARs (CP-AMPARs) mediate glutamatergic transmission at the adult auditory hair cell synapse. Overexcitation of the terminal causes Ca 2+ accumulation and swelling that can be prevented by blocking CP-AMPARs. We demonstrate that CP-AMPARs mediate transmission at this first-order sensory synapse and that limiting Ca 2+ accumulation in the terminal may protect against hearing loss. Copyright © 2017 the authors 0270-6474/17/376162-14$15.00/0.

The immunological synapse: the gateway to the HIV reservoir

PubMed Central

Kulpa, Deanna A; Brehm, Jessica H; Fromentin, Rémi; Cooper, Anthony; Cooper, Colleen; Ahlers, Jeffrey; Chomont, Nicolas; Sékaly, Rafick-Pierre

2013-01-01

A major challenge in the development of a cure for human immunodeficiency virus (HIV) has been the incomplete understanding of the basic mechanisms underlying HIV persistence during antiretroviral therapy. It is now realized that the establishment of a latently infected reservoir refractory to immune system recognition has thus far hindered eradication efforts. Recent investigation into the innate immune response has shed light on signaling pathways downstream of the immunological synapse critical for T-cell activation and establishment of T-cell memory. This has led to the understanding that the cell-to-cell contacts observed in an immunological synapse that involve the CD4+ T cell and antigen-presenting cell or T-cell–T-cell interactions enhance efficient viral spread and facilitate the induction and maintenance of latency in HIV-infected memory T cells. This review focuses on recent work characterizing the immunological synapse and the signaling pathways involved in T-cell activation and gene regulation in the context of HIV persistence. PMID:23772628

Synaptotagmin 7 confers frequency invariance onto specialized depressing synapses

NASA Astrophysics Data System (ADS)

Turecek, Josef; Jackman, Skyler L.; Regehr, Wade G.

2017-11-01

At most synapses in the brain, short-term plasticity dynamically modulates synaptic strength. Rapid frequency-dependent changes in synaptic strength have key roles in sensory adaptation, gain control and many other neural computations. However, some auditory, vestibular and cerebellar synapses maintain constant strength over a wide range of firing frequencies, and as a result efficiently encode firing rates. Despite its apparent simplicity, frequency-invariant transmission is difficult to achieve because of inherent synaptic nonlinearities. Here we study frequency-invariant transmission at synapses from Purkinje cells to deep cerebellar nuclei and at vestibular synapses in mice. Prolonged activation of these synapses leads to initial depression, which is followed by steady-state responses that are frequency invariant for their physiological activity range. We find that synaptotagmin 7 (Syt7), a calcium sensor for short-term facilitation, is present at both synapses. It was unclear why a sensor for facilitation would be present at these and other depressing synapses. We find that at Purkinje cell and vestibular synapses, Syt7 supports facilitation that is normally masked by depression, which can be revealed in wild-type mice but is absent in Syt7 knockout mice. In wild-type mice, facilitation increases with firing frequency and counteracts depression to produce frequency-invariant transmission. In Syt7-knockout mice, Purkinje cell and vestibular synapses exhibit conventional use-dependent depression, weakening to a greater extent as the firing frequency is increased. Presynaptic rescue of Syt7 expression restores both facilitation and frequency-invariant transmission. Our results identify a function for Syt7 at synapses that exhibit overall depression, and demonstrate that facilitation has an unexpected and important function in producing frequency-invariant transmission.

Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study.

PubMed

Tiveron, Marcos Gradim; Pomerantzeff, Pablo Maria Alberto; de Lourdes Higuchi, Maria; Reis, Marcia Martins; de Jesus Pereira, Jaqueline; Kawakami, Joyce Tieko; Ikegami, Renata Nishiyama; de Almeida Brandao, Carlos Manuel; Jatene, Fabio Biscegli

2017-04-21

The etiology of myxomatous mitral valve degeneration (MVD) is not fully understood and may depend on time or environmental factors for which the interaction of infectious agents has not been documented. The purpose of the study is to analyze the effect of Mycoplasma pneumoniae (Mp), Chlamydophila pneumoniae (Cp) and Borrelia burgdorferi (Bb) on myxomatous mitral valve degeneration pathogenesis and establish whether increased in inflammation and collagen degradation in myxomatous mitral valve degeneration etiopathogenesis. An immunohistochemical test was performed to detect the inflammatory cells (CD20, CD45, CD68) and Mp, Bb and MMP9 antigens in two groups. The in situ hybridization was performed to detect Chlamydophila pneumoniae and the bacteria study was performed using transmission electron microscopy. Group 1 (n = 20), surgical specimen composed by myxomatous mitral valve degeneration, and group 2 (n = 20), autopsy specimen composed by normal mitral valve. The data were analyzed using SigmaStat version 20 (SPSS Inc., Chicago, IL, USA). The groups were compared using Student's t test, Mann-Whitney test. A correlation analysis was performed using Spearman's correlation test. P values lower than 0.05 were considered statistically significant. By immunohistochemistry, there was a higher inflammatory cells/mm2 for CD20 and CD45 in group 1, and CD68 in group 2. Higher number of Mp and Cp antigens was observed in group 1 and more Bb antigens was detected in group 2. The group 1 exhibited a positive correlation between the Bb and MVD percentage, between CD45 and Mp, and between MMP9 with Mp. These correlations were not observed in the group 2. Electron microscopy revealed the presence of structures compatible with microorganisms that feature Borrelia and Mycoplasma characteristics. The presence of infectious agents, inflammatory cells and collagenases in mitral valves appear to contribute to the pathogenesis of MVD. Mycoplasma pneumoniae was strongly related with myxomatous mitral valve degeneration. Despite of low percentage of Borrelia burgdorferi in MD group, this agent was correlated with myxomatous degeneration and this may occour due synergistic actions between these infectious agents likely contribute to collagen degradation.

Neuronal somata and extrasomal compartments play distinct roles during synapse formation between Lymnaea neurons.

PubMed

Xu, Fenglian; Luk, Collin C; Wiersma-Meems, Ryanne; Baehre, Kelly; Herman, Cameron; Zaidi, Wali; Wong, Noelle; Syed, Naweed I

2014-08-20

Proper synapse formation is pivotal for all nervous system functions. However, the precise mechanisms remain elusive. Moreover, compared with the neuromuscular junction, steps regulating the synaptogenic program at central cholinergic synapses remain poorly defined. In this study, we identified different roles of neuronal compartments (somal vs extrasomal) in chemical and electrical synaptogenesis. Specifically, the electrically synapsed Lymnaea pedal dorsal A cluster neurons were used to study electrical synapses, whereas chemical synaptic partners, visceral dorsal 4 (presynaptic, cholinergic), and left pedal dorsal 1 (LPeD1; postsynaptic) were explored for chemical synapse formation. Neurons were cultured in a soma-soma or soma-axon configuration and synapses explored electrophysiologically. We provide the first direct evidence that electrical synapses develop in a soma-soma, but not soma-axon (removal of soma) configuration, indicating the requirement of gene transcription regulation in the somata of both synaptic partners. In addition, the soma-soma electrical coupling was contingent upon trophic factors present in Lymnaea brain-conditioned medium. Further, we demonstrate that chemical (cholinergic) synapses between soma-soma and soma-axon pairs were indistinguishable, with both exhibiting a high degree of contact site and target cell type specificity. We also provide direct evidence that presynaptic cell contact-mediated, clustering of postsynaptic cholinergic receptors at the synaptic site requires transmitter-receptor interaction, receptor internalization, and a protein kinase C-dependent lateral migration toward the contact site. This study provides novel insights into synaptogenesis between central neurons revealing both distinct and synergistic roles of cell-cell signaling and extrinsic trophic factors in executing the synaptogenic program. Copyright © 2014 the authors 0270-6474/14/3411304-12$15.00/0.

T cell costimulation by chemokine receptors.

PubMed

Molon, Barbara; Gri, Giorgia; Bettella, Monica; Gómez-Moutón, Concepción; Lanzavecchia, Antonio; Martínez-A, Carlos; Mañes, Santos; Viola, Antonella

2005-05-01

Signals mediated by chemokine receptors may compete with T cell receptor stop signals and determine the duration of T cell-antigen-presenting cell interactions. Here we show that during T cell stimulation by antigen-presenting cells, T cell chemokine receptors coupled to G(q) and/or G(11) protein were recruited to the immunological synapse by a G(i)-independent mechanism. When chemokine receptors were sequestered at the immunological synapse, T cells became insensitive to chemotactic gradients, formed more stable conjugates and finally responded with enhanced proliferation and cytokine production. We suggest that chemokine receptor trapping at the immunological synapse enhances T cell activation by improving T cell-antigen-presenting cell attraction and impeding the 'distraction' of successfully engaged T cells by other chemokine sources.

Imaging Vesicular Traffic at the Immune Synapse.

PubMed

Bouchet, Jérôme; Del Río-Iñiguez, Iratxe; Alcover, Andrés

2017-01-01

Immunological synapse formation is the result of a profound T cell polarization process that involves the coordinated action of the actin and microtubule cytoskeleton, as well as intracellular vesicle traffic. Endosomal vesicle traffic ensures the targeting of the T cell receptor (TCR) and various signaling molecules to the synapse, being necessary for the generation of signaling complexes downstream of the TCR. Here we describe the microscopy imaging methods that we currently use to unveil how TCR and signaling molecules are associated with endosomal compartments and deliver their cargo to the immunological synapse.

Tuning B cell responses to antigens by cell polarity and membrane trafficking.

PubMed

Del Valle Batalla, Felipe; Lennon-Dumenil, Ana-María; Yuseff, María-Isabel

2018-06-20

The capacity of B lymphocytes to produce specific antibodies, particularly broadly neutralizing antibodies that provide immunity to viral pathogens has positioned them as valuable therapeutic targets for immunomodulation. To become competent as antibody secreting cells, B cells undergo a series of activation steps, which are triggered by the recognition of antigens frequently displayed on the surface of other presenting cells. Such antigens elicit the formation of an immune synapse (IS), where local cytoskeleton rearrangements coupled to mechanical forces and membrane trafficking orchestrate the extraction and processing of antigens in B cells. In this review, we discuss the molecular mechanisms that regulate polarized membrane trafficking and mechanical properties of the immune synapse, as well as the potential extracellular cues from the environment, which may impact the ability of B cells to sense and acquire antigens at the immune synapse. An integrated view of the diverse cellular mechanisms that shape the immune synapse will provide a better understanding on how B cells are efficiently activated. Copyright © 2018 Elsevier Ltd. All rights reserved.

Simulations of centriole of polarized centrosome as a monopole antenna in immune and viral synapses.

PubMed

Dvorak, Josef; Melichar, Bohuslav; Filipova, Alzbeta; Grimova, Jana; Grimova, Nela; Rozsypalova, Aneta; Buka, David; Voboril, Rene; Zapletal, Radek; Buchler, Tomas; Richter, Igor; Buka, David

2018-01-01

The immune synapse (IS) is a temporary interface between an antigen-presenting cell and an effector lymphocyte. Viral synapse is a molecularly organized cellular junction that is structurally similar to the IS. Primary cilium is considered as a functional homologue of the IS due to the morphological and functional similarities in architecture between both micotubule structures. It has been hypothesized that endogenous electromagnetic field in the cell is generated by a unique cooperating system between mitochondria and microtubules. We are extending this prior hypothesis of the endogenous electromagnetic field in the cell postulating that polarized centriole in immune and viral synapse could serve as a monopole antenna. This is an addition to our hypothesis that primary cilium could serve as a monopole antenna. We simulated the distribution of electric field of centriole of polarized centrosome as a monopole antenna in immune and viral synapse. Very weak electromagnetic field of polarized centriole of CD8+ T lymphocyte in IS can contribute to the transport of cytolytic granules into the attacked (cancer) cell. Analogically, very weak electromagnetic field of polarized centriole in viral synapse of infected CD4 cells can aid the transport of viruses (human immunodeficiency virus) to non-infected CD4 cells. We hypothesized that healthy organisms need these monopole antennas. If, during the neoplastic transformation, healthy cells lose monopole antennas in form of primary cilia, the IS aims to replace them by monopole antennas of polarized centrioles in IS to restore homeostasis.

The need to connect: on the cell biology of synapses, behaviors, and networks in science

PubMed Central

Colón-Ramos, Daniel A.

2016-01-01

My laboratory is interested in the cell biology of the synapse. Synapses, which are points of cellular communication between neurons, were first described by Santiago Ramón y Cajal as “protoplasmic kisses that appear to constitute the final ecstasy of an epic love story.” Who would not want to work on that?! My lab examines the biological mechanisms neurons use to find and connect to each other. How are synapses formed during development, maintained during growth, and modified during learning? In this essay, I reflect about my scientific journey to the synapse, the cell biological one, but also a metaphorical synapse—my role as a point of contact between the production of knowledge and its dissemination. In particular, I discuss how the architecture of scientific networks propels knowledge production but can also exclude certain groups in science. PMID:27799494

TexMi: Development of Tissue-Engineered Textile-Reinforced Mitral Valve Prosthesis

PubMed Central

Moreira, Ricardo; Gesche, Valentine N.; Hurtado-Aguilar, Luis G.; Schmitz-Rode, Thomas; Frese, Julia

2014-01-01

Mitral valve regurgitation together with aortic stenosis is the most common valvular heart disease in Europe and North America. Mechanical and biological prostheses available for mitral valve replacement have significant limitations such as the need of a long-term anticoagulation therapy and failure by calcifications. Both types are unable to remodel, self-repair, and adapt to the changing hemodynamic conditions. Moreover, they are mostly designed for the aortic position and do not reproduce the native annular-ventricular continuity, resulting in suboptimal hemodynamics, limited durability, and gradually decreasing ventricular pumping efficiency. A tissue-engineered heart valve specifically designed for the mitral position has the potential to overcome the limitations of the commercially available substitutes. For this purpose, we developed the TexMi, a living textile-reinforced mitral valve, which recapitulates the key elements of the native one: annulus, asymmetric leaflets (anterior and posterior), and chordae tendineae to maintain the native annular-ventricular continuity. The tissue-engineered valve is based on a composite scaffold consisting of the fibrin gel as a cell carrier and a textile tubular structure with the twofold task of defining the gross three-dimensional (3D) geometry of the valve and conferring mechanical stability. The TexMi valves were molded with ovine umbilical vein cells and stimulated under dynamic conditions for 21 days in a custom-made bioreactor. Histological and immunohistological stainings showed remarkable tissue development with abundant aligned collagen fibers and elastin deposition. No cell-mediated tissue contraction occurred. This study presents the proof-of-principle for the realization of a tissue-engineered mitral valve with a simple and reliable injection molding process readily adaptable to the patient's anatomy and pathological situation by producing a patient-specific rapid prototyped mold. PMID:24665896

Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision

PubMed Central

Hovhannisyan, Anahit; Kung, Jennifer; Lee, Seungjun; Lee, Dae Yeong; Huie, Philip; Dalal, Roopa; Palanker, Daniel

2017-01-01

Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring. SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support the idea that bipolar cells might be able to synapse with reintroduced photoreceptors, thereby restoring vision in patients blinded by retinal degeneration. PMID:28373392

Ultrastructure of electrophysiologically-characterized synapses formed by serotonergic raphe neurons in culture.

PubMed

Johnson, M D; Yee, A G

1995-08-01

Recent electrophysiological investigations in this laboratory have shown that cultured mesopontine serotonergic neurons from neonatal rats evoke serotonergic and/or glutamatergic responses in themselves and in non-serotonergic neurons. Serotonergic nerve terminals in vivo are heterogeneous with respect to vesicle type, synaptic structure, and the frequency with which they form conventional synaptic contacts, but the functional correlates of this heterogeneity are unclear. We have therefore examined the ultrastructure of electrophysiologically-characterized synapses formed by cultured serotonergic neurons, and have compared the findings with the ultrastructural characteristics of serotonergic synapses reported in vivo. Dissociated rat serotonergic neurons in microcultures were identified by serotonin immunocytochemistry or by uptake of the autofluorescent serotonin analogue 5,7-dihydroxytryptamine, and were subsequently processed for electron microscopy. Unlabeled axon terminals formed numerous synapses on serotonin-immunoreactive somata and dendrites. Serotonin-immunoreactive axon terminals formed synapses on the somata, dendrites and somatodendritic spine-like appendages of serotonergic and non-serotonergic neurons. In microcultures containing a solitary serotonergic neuron that evoked glutamatergic or serotonergic/glutamatergic autaptic responses, both symmetric and asymmetric synapses were present. In addition to large dense core vesicles, individual neurons contained either microcanaliculi and microvesicles, clear round vesicles, or clear pleiomorphic vesicles. For a given cell, however, the subtypes of vesicles present in each axon terminal were similar. Thus, dissociated serotonergic and non-serotonergic raphe neurons formed functional, morphological synapses in culture. A direct examination of both the synaptic physiology and ultrastructure of single cultured serotonergic neurons indicated that these cells released serotonin and glutamate at synapses that were morphologically similar to synapses formed by serotonergic neurons in vivo. The findings also suggested that individual serotonergic neurons differ with respect to synaptic vesicle morphology, and are capable of simultaneously forming symmetric and asymmetric synapses with target cells.

Inhibition of Repulsive Guidance Molecule, RGMa, Increases Afferent Synapse Formation with Auditory Hair Cells

PubMed Central

Brugeaud, Aurore; Tong, Mingjie; Luo, Li; Edge, Albert S.B.

2017-01-01

The peripheral fibers that extend from auditory neurons to hair cells are sensitive to damage, and replacement of the fibers and their afferent synapse with hair cells would be of therapeutic interest. Here, we show that RGMa, a repulsive guidance molecule previously shown to play a role in the development of the chick visual system, is expressed in the developing, newborn, and mature mouse inner ear. The effect of RGMa on synaptogenesis between afferent neurons and hair cells, from which afferent connections had been removed, was assessed. Contact of neural processes with hair cells and elaboration of postsynaptic densities at sites of the ribbon synapse were increased by treatment with a blocking antibody to RGMa, and pruning of auditory fibers to achieve the mature branching pattern of afferent neurons was accelerated. Inhibition by RGMa could thus explain why auditory neurons have a low capacity to regenerate peripheral processes: postnatal spiral ganglion neurons retain the capacity to send out processes that respond to signals for synapse formation, but expression of RGMa postnatally appears to be detrimental to regeneration of afferent hair cell innervation and antagonizes synaptogenesis. Increased synaptogenesis after inhibition of RGMa suggests that manipulation of guidance or inhibitory factors may provide a route to increase formation of new synapses at deafferented hair cells. PMID:24123853

Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-β oligomers.

PubMed

McHale-Owen, Harriet; Bate, Clive

2018-03-01

The production of amyloid-β (Aβ) is the key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of Aβ within the brain cause synapse degeneration and the dementia that is characteristic of AD. Here the factors that affect the release of disease-relevant forms Aβ were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released soluble Aβ oligomers that caused synapse damage in cultured neurons. Supernatants from 7PA2 cells treated with the cholesterol synthesis inhibitor squalestatin contained similar concentrations of Aβ 42 to control cells but did not cause synapse damage in neuronal cultures. These supernatants contained reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers. Treatment of 7PA2 cells with platelet-activating factor (PAF) antagonists had similar effects; it reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. PAF activated cholesterol ester hydrolases (CEH), enzymes that released cholesterol from stores of cholesterol esters. Inhibition of CEH also reduced concentrations of Aβ 42 oligomers and increased concentrations of Aβ 42 monomers in cell supernatants. The Aβ monomers produced by treated cells protected neurons against Aβ oligomer-induced synapse damage. These studies indicate that pharmacological manipulation of cells can alter the ratio of Aβ monomer:oligomer released and consequently their effects on synapses. Copyright © 2017 Elsevier B.V. All rights reserved.

Classification of Mouse Retinal Bipolar Cells: Type-Specific Connectivity with Special Reference to Rod-Driven AII Amacrine Pathways

PubMed Central

Tsukamoto, Yoshihiko; Omi, Naoko

2017-01-01

We confirmed the classification of 15 morphological types of mouse bipolar cells by serial section transmission electron microscopy and characterized each type by identifying chemical synapses and gap junctions at axon terminals. Although whether the previous type 5 cells consist of two or three types was uncertain, they are here clustered into three types based on the vertical distribution of axonal ribbons. Next, while two groups of rod bipolar (RB) cells, RB1, and RB2, were previously proposed, we clarify that a half of RB1 cells have the intermediate characteristics, suggesting that these two groups comprise a single RB type. After validation of bipolar cell types, we examined their relationship with amacrine cells then particularly with AII amacrine cells. We found a strong correlation between the number of amacrine cell synaptic contacts and the number of bipolar cell axonal ribbons. Formation of bipolar cell output at each ribbon synapse may be effectively regulated by a few nearby inhibitory inputs of amacrine cells which are chosen from among many amacrine cell types. We also found that almost all types of ON cone bipolar cells frequently have a minor group of midway ribbons along the axon passing through the OFF sublamina as well as a major group of terminal ribbons in the ON sublamina. AII amacrine cells are connected to five of six OFF bipolar cell types via conventional chemical synapses and seven of eight ON (cone) bipolar cell types via electrical synapses (gap junctions). However, the number of synapses is dependent on bipolar cell types. Type 2 cells have 69% of the total number of OFF bipolar chemical synaptic contacts with AII amacrine cells and type 6 cells have 46% of the total area of ON bipolar gap junctions with AII amacrine cells. Both type 2 and 6 cells gain the greatest access to AII amacrine cell signals also share those signals with other types of bipolar cells via networked gap junctions. These findings imply that the most sensitive scotopic signal may be conveyed to the center by ganglion cells that have the most numerous synapses with type 2 and 6 cells. PMID:29114208

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output

PubMed Central

Shao, Zuoyi; Puche, Adam C.; Liu, Shaolin

2012-01-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABAA receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs. PMID:22592311

Intraglomerular inhibition shapes the strength and temporal structure of glomerular output.

PubMed

Shao, Zuoyi; Puche, Adam C; Liu, Shaolin; Shipley, Michael T

2012-08-01

Odor signals are transmitted to the olfactory bulb by olfactory nerve (ON) synapses onto mitral/tufted cells (MCs) and external tufted cells (ETCs). ETCs, in turn, provide feedforward excitatory input to MCs. MC and ETCs are also regulated by inhibition: intraglomerular and interglomerular inhibitory circuits act at MC and ETC apical dendrites; granule cells (GCs) inhibit MC lateral dendrites via the MC→GC→MC circuit. We investigated the contribution of intraglomerular inhibition to MC and ETCs responses to ON input. ON input evokes initial excitation followed by early, strongly summating inhibitory postsynaptic currents (IPSCs) in MCs; this is followed by prolonged, intermittent IPSCs. The N-methyl-d-aspartate receptor antagonist dl-amino-5-phosphovaleric acid, known to suppress GABA release by GCs, reduced late IPSCs but had no effect on early IPSCs. In contrast, selective intraglomerular block of GABA(A) receptors eliminated all early IPSCs and caused a 5-fold increase in ON-evoked MC spiking and a 10-fold increase in response duration. ETCs also receive intraglomerular inhibition; blockade of inhibition doubled ETC spike responses. By reducing ETC excitatory drive and directly inhibiting MCs, intraglomerular inhibition is a key factor shaping the strength and temporal structure of MC responses to sensory input. Sensory input generates an intraglomerular excitation-inhibition sequence that limits MC spike output to a brief temporal window. Glomerular circuits may dynamically regulate this input-output window to optimize MC encoding across sniff-sampled inputs.

The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late-Stage T Cells

PubMed Central

Awerkiew, Sabine; Schmidt, Annette; Hombach, Andreas A.; Pfister, Herbert; Abken, Hinrich

2012-01-01

Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1+ CD57+ CD7− phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter. PMID:22292024

Regulation of vesicular traffic at the T cell immune synapse: lessons from the primary cilium.

PubMed

Finetti, Francesca; Onnis, Anna; Baldari, Cosima T

2015-03-01

The signals that orchestrate the process of T cell activation are coordinated at the specialized interface that forms upon contact with an antigen presenting cell displaying a specific MHC-associated peptide ligand, known as the immune synapse. The central role of vesicular traffic in the assembly of the immune synapse has emerged only in recent years with the finding that sustained T-cell receptor (TCR) signaling involves delivery of TCR/CD3 complexes from an intracellular pool associated with recycling endosomes. A number of receptors as well as membrane-associated signaling mediators have since been demonstrated to exploit this process to localize to the immune synapse. Here, we will review our current understanding of the mechanisms responsible for TCR recycling, with a focus on the intraflagellar transport system, a multimolecular complex that is responsible for the assembly and function of the primary cilium which we have recently implicated in polarized endosome recycling to the immune synapse. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sickle cell anemia and mitral valve replacement. Case report.

PubMed

Bomfim, V; Ribeiro, A; Gouvea, F; Pereira, J; Björk, V

1989-01-01

An 8-year-old black boy with sickle cell disease and severe hemolytic anemia crisis (95% hemoglobin S) also had mitral incompetence due to rheumatic valve disease. A 27 mm monostrut Björk-Shiley valve prosthesis was implanted after partial exchange transfusions had reduced the hemoglobin S to less than 40%. High-flow normothermic perfusion was used during extracorporeal circulation, with care taken to avoid hypoxia and acidosis. Postoperative recovery was uneventful.

Dressing up Nanoparticles: A Membrane Wrap to Induce Formation of the Virological Synapse

PubMed Central

Yu, Xinwei; Xu, Fangda; Ramirez, Nora-Guadalupe P.; Kijewski, Suzanne D. G.; Akiyama, Hisashi; Gummuluru, Suryaram; Reinhard, Björn M.

2015-01-01

Next generation nanoparticle-based drug delivery systems require the ability to target specific organelles or subcellular regions in selected target cells. Human immunodeficiency virus type I (HIV-1) particles are evolutionarily optimized nanocarriers that have evolved to avoid intracellular degradation and achieve enrichment at the synapse between mature dendritic cells (mDCs) and T cells by subverting cellular trafficking mechanisms. This study demonstrates that integration of the glycosphingolipid, GM3, in a membrane around a solid nanoparticle (NP) core is sufficient to recapitulate key aspects of the virus particle trafficking in mDCs. GM3 presenting artificial virus NPs (GM3-AVNs) accumulate in CD169+, CD81+, non-lysosomal compartments in an actin-dependent process that mimics the sequestration of HIV-1. Live-cell optical tracking studies reveal a preferential recruitment and arrest of surface scanning CD4+ T cells in direct vicinity to the AVN-enriched compartments. The formed mDC-T cell conjugates exhibit strong morphological similarities between the GM3-AVN-containing mDC-T cell synapse and the HIV-1 virological synapse, indicating that GM3-CD169 interactions alone are sufficient for establishing the mDC-T cell virological synapse. These results emphasize the potential of the GM3-AVN approach for providing therapeutic access to a key step of the host immune response – formation of the synaptic junction between an antigen-presenting cell (mDC) and T cells – for modulating and controlling immune responses. PMID:25853367

Automatic analysis and quantification of fluorescently labeled synapses in microscope images

NASA Astrophysics Data System (ADS)

Yona, Shai; Katsman, Alex; Orenbuch, Ayelet; Gitler, Daniel; Yitzhaky, Yitzhak

2011-09-01

The purpose of this work is to classify and quantify synapses and their properties in the cultures of a mouse's hippocampus, from images acquired by a fluorescent microscope. Quantification features include the number of synapses, their intensity and their size characteristics. The images obtained by the microscope contain hundreds to several thousands of synapses with various elliptic-like shape features and intensities. These images also include other features such as glia cells and other biological objects beyond the focus plane; those features reduce the visibility of the synapses and interrupt the segmentation process. The proposed method comprises several steps, including background subtraction, identification of suspected centers of synapses as local maxima of small neighborhoods, evaluation of the tendency of objects to be synapses according to intensity properties at their larger neighborhoods, classification of detected synapses into categories as bulks or single synapses and finally, delimiting the borders of each synapse.

Examination of mitral regurgitation with a goat heart model for the development of intelligent artificial papillary muscle.

PubMed

Shiraishi, Y; Yambe, T; Yoshizawa, M; Hashimoto, H; Yamada, A; Miura, H; Hashem, M; Kitano, T; Shiga, T; Homma, D

2012-01-01

Annuloplasty for functional mitral or tricuspid regurgitation has been made for surgical restoration of valvular diseases. However, these major techniques may sometimes be ineffective because of chamber dilation and valve tethering. We have been developing a sophisticated intelligent artificial papillary muscle (PM) by using an anisotropic shape memory alloy fiber for an alternative surgical reconstruction of the continuity of the mitral structural apparatus and the left ventricular myocardium. This study exhibited the mitral regurgitation with regard to the reduction in the PM tension quantitatively with an originally developed ventricular simulator using isolated goat hearts for the sophisticated artificial PM. Aortic and mitral valves with left ventricular free wall portions of isolated goat hearts (n=9) were secured on the elastic plastic membrane and statically pressurized, which led to valvular leaflet-papillary muscle positional change and central mitral regurgitation. PMs were connected to the load cell, and the relationship between the tension of regurgitation and PM tension were measured. Then we connected the left ventricular specimen model to our hydraulic ventricular simulator and achieved hemodynamic simulation with the controlled tension of PMs.

Subunit- and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina

PubMed Central

Zhang, Jun; Diamond, Jeffrey S.

2014-01-01

Retinal ganglion cells (RGCs) receive excitatory glutamatergic input from ON and OFF bipolar cells in distinct sublaminae of the inner plexiform layer (IPL). AMPA and NMDA receptors (AMPARs and NMDARs) mediate excitatory inputs in both synaptic layers, but specific roles for NMDARs at RGC synapses remain unclear. NMDARs comprise NR1 and NR2 subunits and are anchored by membrane associated guanylate kinases (MAGUKs), but it is unknown whether particular NR2 subunits associate preferentially with particular NR1 splice variants and MAGUKs. Here, we used postembedding immunogold electron microscopy (EM) techniques to examine the subsynaptic localization of NMDAR subunits and MAGUKs at ON and OFF synapses onto rat RGCs. We found that the NR2A subunit, the NR1C2‘ splice variant and MAGUKs PSD-95 and PSD-93 are localized to the postsynaptic density (PSD), preferentially at OFF synapses, whereas the NR2B subunit, the NR1C2 splice variant and the MAGUK SAP102 are localized perisynaptically, with NR2B exhibiting a preference for ON synapses. Consistent with these anatomical data, spontaneous EPSCs (sEPSCs) recorded from OFF cells exhibited an NMDAR component that was insensitive to the NR2B antagonist Ro 25-6981. In ON cells, sEPSCs expressed an NMDAR component, partially sensitive to Ro 25-6981, only when glutamate transport was inhibited, indicating perisynaptic expression of NR2B NMDARs. These results provide the first evidence for preferential association of particular NR1 splice variants, NR2 subunits and MAGUKs at central synapses and suggest that different NMDAR subtypes may play specific roles at functionally distinct synapses in the retinal circuitry. PMID:19339621

Live Imaging of HIV-1 Transfer across T Cell Virological Synapse to Epithelial Cells that Promotes Stromal Macrophage Infection.

PubMed

Real, Fernando; Sennepin, Alexis; Ganor, Yonatan; Schmitt, Alain; Bomsel, Morgane

2018-05-08

During sexual intercourse, HIV-1 crosses epithelial barriers composing the genital mucosa, a poorly understood feature that requires an HIV-1-infected cell vectoring efficient mucosal HIV-1 entry. Therefore, urethral mucosa comprising a polarized epithelium and a stroma composed of fibroblasts and macrophages were reconstructed in vitro. Using this system, we demonstrate by live imaging that efficient HIV-1 transmission to stromal macrophages depends on cell-mediated transfer of the virus through virological synapses formed between HIV-1-infected CD4 + T cells and the epithelial cell mucosal surface. We visualized HIV-1 translocation through mucosal epithelial cells via transcytosis in regions where virological synapses occurred. In turn, interleukin-13 is secreted and HIV-1 targets macrophages, which develop a latent state of infection reversed by lipopolysaccharide (LPS) activation. The live observation of virological synapse formation reported herein is key in the design of vaccines and antiretroviral therapies aimed at blocking HIV-1 access to cellular reservoirs in genital mucosa. Copyright © 2018. Published by Elsevier Inc.

Visualization of HIV T Cell Virological Synapses and Virus-Containing Compartments by Three-Dimensional Correlative Light and Electron Microscopy

PubMed Central

Wang, Lili; Eng, Edward T.; Law, Kenneth; Gordon, Ronald E.; Rice, William J.

2016-01-01

ABSTRACT Virological synapses (VS) are adhesive structures that form between infected and uninfected cells to enhance the spread of HIV-1. During T cell VS formation, viral proteins are actively recruited to the site of cell-cell contact where the viral material is efficiently translocated to target cells into heterogeneous, protease-resistant, antibody-inaccessible compartments. Using correlative light and electron microscopy (CLEM), we define the membrane topography of the virus-containing compartments (VCC) where HIV is found following VS-mediated transfer. Focused ion beam scanning electron microscopy (FIB-SEM) and serial sectioning transmission electron microscopy (SS-TEM) were used to better resolve the fluorescent Gag-containing structures within the VCC. We found that small punctate fluorescent signals correlated with single viral particles in enclosed vesicular compartments or surface-localized virus particles and that large fluorescent signals correlated with membranous Gag-containing structures with unknown pathological function. CLEM imaging revealed distinct pools of newly deposited viral proteins within endocytic and nonendocytic compartments in VS target T cells. IMPORTANCE This study directly correlates individual virus-associated objects observed in light microscopy with ultrastructural features seen by electron microscopy in the HIV-1 virological synapse. This approach elucidates which infection-associated ultrastructural features represent bona fide HIV protein complexes. We define the morphology of some HIV cell-to-cell transfer intermediates as true endocytic compartments and resolve unique synapse-associated viral structures created by transfer across virological synapses. PMID:27847357

Boltzmann Energy-based Image Analysis Demonstrates that Extracellular Domain Size Differences Explain Protein Segregation at Immune Synapses

PubMed Central

Burroughs, Nigel J.; Köhler, Karsten; Miloserdov, Vladimir; Dustin, Michael L.; van der Merwe, P. Anton; Davis, Daniel M.

2011-01-01

Immune synapses formed by T and NK cells both show segregation of the integrin ICAM1 from other proteins such as CD2 (T cell) or KIR (NK cell). However, the mechanism by which these proteins segregate remains unclear; one key hypothesis is a redistribution based on protein size. Simulations of this mechanism qualitatively reproduce observed segregation patterns, but only in certain parameter regimes. Verifying that these parameter constraints in fact hold has not been possible to date, this requiring a quantitative coupling of theory to experimental data. Here, we address this challenge, developing a new methodology for analysing and quantifying image data and its integration with biophysical models. Specifically we fit a binding kinetics model to 2 colour fluorescence data for cytoskeleton independent synapses (2 and 3D) and test whether the observed inverse correlation between fluorophores conforms to size dependent exclusion, and further, whether patterned states are predicted when model parameters are estimated on individual synapses. All synapses analysed satisfy these conditions demonstrating that the mechanisms of protein redistribution have identifiable signatures in their spatial patterns. We conclude that energy processes implicit in protein size based segregation can drive the patternation observed in individual synapses, at least for the specific examples tested, such that no additional processes need to be invoked. This implies that biophysical processes within the membrane interface have a crucial impact on cell∶cell communication and cell signalling, governing protein interactions and protein aggregation. PMID:21829338

Reciprocal synapses between outer hair cells and their afferent terminals: evidence for a local neural network in the mammalian cochlea.

PubMed

Thiers, Fabio A; Nadol, Joseph B; Liberman, M Charles

2008-12-01

Cochlear outer hair cells (OHCs) serve both as sensory receptors and biological motors. Their sensory function is poorly understood because their afferent innervation, the type-II spiral ganglion cell, has small unmyelinated axons and constitutes only 5% of the cochlear nerve. Reciprocal synapses between OHCs and their type-II terminals, consisting of paired afferent and efferent specialization, have been described in the primate cochlea. Here, we use serial and semi-serial-section transmission electron microscopy to quantify the nature and number of synaptic interactions in the OHC area of adult cats. Reciprocal synapses were found in all OHC rows and all cochlear frequency regions. They were more common among third-row OHCs and in the apical half of the cochlea, where 86% of synapses were reciprocal. The relative frequency of reciprocal synapses was unchanged following surgical transection of the olivocochlear bundle in one cat, confirming that reciprocal synapses were not formed by efferent fibers. In the normal ear, axo-dendritic synapses between olivocochlear terminals and type-II terminals and/or dendrites were as common as synapses between olivocochlear terminals and OHCs, especially in the first row, where, on average, almost 30 such synapses were seen in the region under a single OHC. The results suggest that a complex local neuronal circuitry in the OHC area, formed by the dendrites of type-II neurons and modulated by the olivocochlear system, may be a fundamental property of the mammalian cochlea, rather than a curiosity of the primate ear. This network may mediate local feedback control of, and bidirectional communication among, OHCs throughout the cochlear spiral.

Electron Microscopic Analysis of Hippocampal Axo‐Somatic Synapses in a Chronic Stress Model for Depression

PubMed Central

Csabai, Dávid; Seress, László; Varga, Zsófia; Ábrahám, Hajnalka; Miseta, Attila; Wiborg, Ove

2016-01-01

ABSTRACT Stress can alter the number and morphology of excitatory synapses in the hippocampus, but nothing is known about the effect of stress on inhibitory synapses. Here, we used an animal model for depression, the chronic mild stress model, and quantified the number of perisomatic inhibitory neurons and their synapses. We found reduced density of parvalbumin‐positive (PV+) neurons in response to stress, while the density of cholecystokinin‐immunoreactive (CCK+) neurons was unaffected. We did a detailed electron microscopic analysis to quantify the frequency and morphology of perisomatic inhibitory synapses in the hippocampal CA1 area. We analyzed 1100 CA1 pyramidal neurons and 4800 perisomatic terminals in five control and four chronically stressed rats. In the control animals we observed the following parameters: Number of terminals/soma = 57; Number of terminals/100 µm cell perimeter = 10; Synapse/terminal ratio = 32%; Synapse number/100 terminal = 120; Average terminal length = 920nm. None of these parameters were affected by the stress exposure. Overall, these data indicate that despite the depressive‐like behavior and the decrease in the number of perisomatic PV+ neurons in the light microscopic preparations, the number of perisomatic inhibitory synapses on CA1 pyramidal cells was not affected by stress. In the electron microscope, PV+ neurons and the axon terminals appeared to be normal and we did not find any apoptotic or necrotic cells. This data is in sharp contrast to the remarkable remodeling of the excitatory synapses on spines that has been reported in response to stress and depressive‐like behavior. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:27571571

Synaptic transmission and the susceptibility of HIV infection to anti-viral drugs

NASA Astrophysics Data System (ADS)

Komarova, Natalia L.; Levy, David N.; Wodarz, Dominik

2013-07-01

Cell-to-cell viral transmission via virological synapses has been argued to reduce susceptibility of the virus population to anti-viral drugs through multiple infection of cells, contributing to low-level viral persistence during therapy. Using a mathematical framework, we examine the role of synaptic transmission in treatment susceptibility. A key factor is the relative probability of individual virions to infect a cell during free-virus and synaptic transmission, a currently unknown quantity. If this infection probability is higher for free-virus transmission, then treatment susceptibility is lowest if one virus is transferred per synapse, and multiple infection of cells increases susceptibility. In the opposite case, treatment susceptibility is minimized for an intermediate number of virions transferred per synapse. Hence, multiple infection via synapses does not simply lower treatment susceptibility. Without further experimental investigations, one cannot conclude that synaptic transmission provides an additional mechanism for the virus to persist at low levels during anti-viral therapy.

Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning

PubMed Central

Henson, Maile A.; Tucker, Charles J.; Zhao, Meilan; Dudek, Serena M.

2016-01-01

Activity-dependent pruning of synaptic contacts plays a critical role in shaping neuronal circuitry in response to the environment during postnatal brain development. Although there is compelling evidence that shrinkage of dendritic spines coincides with synaptic long-term depression (LTD), and that LTD is accompanied by synapse loss, whether NMDA receptor (NMDAR)-dependent LTD is a required step in the progression toward synapse pruning is still unknown. Using repeated applications of NMDA to induce LTD in dissociated rat neuronal cultures, we found that synapse density, as measured by colocalization of fluorescent markers for pre- and postsynaptic structures, was decreased irrespective of the presynaptic marker used, post-treatment recovery time, and the dendritic location of synapses. Consistent with previous studies, we found that synapse loss could occur without apparent net spine loss or cell death. Furthermore, synapse loss was unlikely to require direct contact with microglia, as the number of these cells was minimal in our culture preparations. Supporting a model by which NMDAR-LTD is required for synapse loss, the effect of NMDA on fluorescence colocalization was prevented by phosphatase and caspase inhibitors. In addition, gene transcription and protein translation also appeared to be required for loss of putative synapses. These data support the idea that NMDAR-dependent LTD is a required step in synapse pruning and contribute to our understanding of the basic mechanisms of this developmental process. PMID:27794462

GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons

PubMed Central

Wu, Xiaoyun; Fu, Yu; Knott, Graham; Lu, Jiangteng; Di Cristo, Graziella

2012-01-01

Accumulating evidence indicates that GABA acts beyond inhibitory synaptic transmission and regulates the development of inhibitory synapses in the vertebrate brain, but the underlying cellular mechanism is not well understood. We have combined live imaging of cortical GABAergic axons across time scales from minutes to days with single-cell genetic manipulation of GABA release to examine its role in distinct steps of inhibitory synapse formation in the mouse neocortex. We have shown previously, by genetic knockdown of GABA synthesis in developing interneurons, that GABA signaling promotes the maturation of inhibitory synapses and axons. Here we found that a complete blockade of GABA release in basket interneurons resulted in an opposite effect, a cell-autonomous increase in axon and bouton density with apparently normal synapse structures. These results not only demonstrate that GABA is unnecessary for synapse formation per se but also uncover a novel facet of GABA in regulating synapse elimination and axon pruning. Live imaging revealed that developing GABAergic axons form a large number of transient boutons, but only a subset was stabilized. Release blockade led to significantly increased bouton stability and filopodia density, increased axon branch extension, and decreased branch retraction. Our results suggest that a major component of GABA function in synapse development is transmission-mediated elimination of subsets of nascent contacts. Therefore, GABA may regulate activity-dependent inhibitory synapse formation by coordinately eliminating certain nascent contacts while promoting the maturation of other nascent synapses. PMID:22219294

Diversity of Spine Synapses in Animals

PubMed Central

Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

2016-01-01

Here we examine the structure of the various types of spine synapses throughout the animal kingdom. Based on available evidence, we suggest that there are two major categories of spine synapses: invaginating and non-invaginating, with distributions that vary among different groups of animals. In the simplest living animals with definitive nerve cells and synapses, the cnidarians and ctenophores, most chemical synapses do not form spine synapses. But some cnidarians have invaginating spine synapses, especially in photoreceptor terminals of motile cnidarians with highly complex visual organs, and also in some mainly sessile cnidarians with rapid prey capture reflexes. This association of invaginating spine synapses with complex sensory inputs is retained in the evolution of higher animals in photoreceptor terminals and some mechanoreceptor synapses. In contrast to invaginating spine synapse, non-invaginating spine synapses have been described only in animals with bilateral symmetry, heads and brains, associated with greater complexity in neural connections. This is apparent already in the simplest bilaterians, the flatworms, which can have well-developed non-invaginating spine synapses in some cases. Non-invaginating spine synapses diversify in higher animal groups. We also discuss the functional advantages of having synapses on spines and more specifically, on invaginating spines. And finally we discuss pathologies associated with spine synapses, concentrating on those systems and diseases where invaginating spine synapses are involved. PMID:27230661

Glial Control of Endocannabinoid Heterosynaptic Modulation in Hypothalamic Magnocellular Neuroendocrine Cells

PubMed Central

Popescu, Ion R.

2013-01-01

Cannabinoid receptors are functionally operant at both glutamate and GABA synapses on hypothalamic magnocellular neuroendocrine cells; however, retrograde endocannabinoid actions are evoked at only glutamate synapses. We tested whether the functional targeting of evoked retrograde endocannabinoid actions to glutamate, and not GABA, synapses on magnocellular neurons is the result of the spatial restriction of extracellular endocannabinoids by astrocytes. Whole-cell GABA synaptic currents were recorded in magnocellular neurons in rat hypothalamic slices following manipulations to reduce glial buffering of extracellular signals. Depolarization- and glucocorticoid-evoked retrograde endocannabinoid suppression of synaptic GABA release was not detected under normal conditions, but occurred in both oxytocin and vasopressin neurons under conditions of attenuated glial coverage and depressed glial metabolic function, suggesting an emergent endocannabinoid modulation of GABA synapses with the loss of astrocyte function. Tonic endocannabinoid suppression of GABA release was insensitive to glial manipulation. Blocking cannabinoid transport mimicked, and increasing the extracellular viscosity reversed, the effect of suppressed glial buffering on the endocannabinoid modulation of GABA release. Evoked, but not tonic, endocannabinoid modulation of GABA synapses was mediated by 2-arachidonoylglycerol. Therefore, depolarization- and glucocorticoid-evoked 2-arachidonoylglycerol release from magnocellular neurons is spatially restricted to glutamate synapses by astrocytes, but spills over onto GABA synapses under conditions of reduced astrocyte buffering; tonic endocannabinoid modulation of GABA release, in contrast, is likely mediated by anandamide and is insensitive to astrocytic buffering. Astrocytes, therefore, provide dynamic control of stimulus-evoked 2-arachidonoylglycerol, but not tonic anandamide, regulation of GABA synaptic inputs to magnocellular neuroendocrine cells under different physiological conditions. PMID:24227742

ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory

PubMed Central

Chiang, Po-Han; Chien, Ta-Chun; Chen, Chih-Cheng; Yanagawa, Yuchio; Lien, Cheng-Chang

2015-01-01

Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons. PMID:25988357

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity.

PubMed

Davenport, A J; Cross, R S; Watson, K A; Liao, Y; Shi, W; Prince, H M; Beavis, P A; Trapani, J A; Kershaw, M H; Ritchie, D S; Darcy, P K; Neeson, P J; Jenkins, M R

2018-02-27

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell. Copyright © 2018 the Author(s). Published by PNAS.

Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity

PubMed Central

Davenport, A. J.; Cross, R. S.; Watson, K. A.; Liao, Y.; Shi, W.; Prince, H. M.; Beavis, P. A.; Trapani, J. A.; Kershaw, M. H.; Ritchie, D. S.; Darcy, P. K.; Jenkins, M. R.

2018-01-01

Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters. Both proximal and distal receptor signaling pathways were induced more rapidly and subsequently decreased more rapidly in carCTL than in tcrCTL. The functional consequence of this rapid signaling in carCTL cells included faster lytic granule recruitment to the immune synapse, correlating with faster detachment of the CTL from the target cell. This study provides a mechanism for how CAR-T cells can debulk large tumor burden quickly and may contribute to further refinement of CAR design for enhancing the quality of signaling and programming of the T cell. PMID:29440406

A spaceflight study of synaptic plasticity in adult rat vestibular maculas

NASA Technical Reports Server (NTRS)

Ross, M. D.

1994-01-01

Behavioral signs of vestibular perturbation in altered gravity have not been well correlated with structural modifications in neurovestibular centers. This ultrastructural research investigated synaptic plasticity in hair cells of adult rat utricular maculas exposed to microgravity for nine days on a space shuttle. The hypothesis was that synaptic plasticity would be more evident in type II hair cells because they are part of a distributed modifying macular circuitry. All rats were shared with other investigators and were subjected to treatments unrelated to this experiment. Maculas were obtained from flight and control rats after shuttle return (R + 0) and nine days post-flight (R + 9). R + 9 rats had chromodacryorrhea, a sign of acute stress. Tissues were prepared for ultrastructural study by conventional methods. Ribbon synapses were counted in fifty serial sections from medial utricular macular regions of three rats of each flight and control group. Counts in fifty additional consecutive sections from one sample in each group established method reliability. All synapses were photographed and located to specific cells on mosaics of entire sections. Pooled data were analyzed statistically. Flown rats showed abnormal posture and movement at R + 0. They had statistically significant increases in total ribbon synapses and in sphere-like ribbons in both kinds of hair cells; in type II cells, pairs of synapses nearly doubled and clusters of 3 to 6 synapses increased twelve-fold. At R + 9, behavioral signs were normal. However, synapse counts remained high in both kinds of hair cells of flight maculas and were elevated in control type II cells. Only counts in type I cells showed statistically significant differences at R + 9. High synaptic counts at R + 9 may have resulted from stress due to experimental treatments. The results nevertheless demonstrate that adult maculas retain the potential for synaptic plasticity. Type II cells exhibited more synaptic plasticity, but space flight induced synaptic plasticity in type I cells.

Deafferented Adult Rod Bipolar Cells Create New Synapses with Photoreceptors to Restore Vision.

PubMed

Beier, Corinne; Hovhannisyan, Anahit; Weiser, Sydney; Kung, Jennifer; Lee, Seungjun; Lee, Dae Yeong; Huie, Philip; Dalal, Roopa; Palanker, Daniel; Sher, Alexander

2017-04-26

Upon degeneration of photoreceptors in the adult retina, interneurons, including bipolar cells, exhibit a plastic response leading to their aberrant rewiring. Photoreceptor reintroduction has been suggested as a potential approach to sight restoration, but the ability of deafferented bipolar cells to establish functional synapses with photoreceptors is poorly understood. Here we use photocoagulation to selectively destroy photoreceptors in adult rabbits while preserving the inner retina. We find that rods and cones shift into the ablation zone over several weeks, reducing the blind spot at scotopic and photopic luminances. During recovery, rod and cone bipolar cells exhibit markedly different responses to deafferentation. Rod bipolar cells extend their dendrites to form new synapses with healthy photoreceptors outside the lesion, thereby restoring visual function in the deafferented retina. Secretagogin-positive cone bipolar cells did not exhibit such obvious dendritic restructuring. These findings are encouraging to the idea of photoreceptor reintroduction for vision restoration in patients blinded by retinal degeneration. At the same time, they draw attention to the postsynaptic side of photoreceptor reintroduction; various bipolar cell types, representing different visual pathways, vary in their response to the photoreceptor loss and in their consequent dendritic restructuring. SIGNIFICANCE STATEMENT Loss of photoreceptors during retinal degeneration results in permanent visual impairment. Strategies for vision restoration based on the reintroduction of photoreceptors inherently rely on the ability of the remaining retinal neurons to correctly synapse with new photoreceptors. We show that deafferented bipolar cells in the adult mammalian retina can reconnect to rods and cones and restore retinal sensitivity at scotopic and photopic luminances. Rod bipolar cells extend their dendrites to form new synapses with healthy rod photoreceptors. These findings support the idea that bipolar cells might be able to synapse with reintroduced photoreceptors, thereby restoring vision in patients blinded by retinal degeneration. Copyright © 2017 the authors 0270-6474/17/374635-10$15.00/0.

Choline acetyltransferase (ChAT) immunoelectron microscopy distinguishes at least three types of efferent synapses in the organ of Corti.

PubMed

Eybalin, M; Pujol, R

1987-01-01

Using anatomical criteria, the olivo-cochlear fibers ending in the organ of Corti (efferent fibers) have recently been separated into two systems: a lateral system innervating principally the inner hair cell (IHC) area and a medial system innervating mainly the outer hair cells (OHCs). Electrophysiological and biochemical experiments suggest that acetylcholine may be a neurotransmitter of these efferent fibers. However, efferent synapses that use acetylcholine as neurotransmitter have not yet been identified at the electron microscopic level. Using a pre-embedding immunoelectron microscopic technique with a monoclonal antibody against choline acetyltransferase (ChAT), we localized ChAT-immunostained fibers below both the IHCs and OHCs. In the inner spiral bundle, one type of ChAT-immunostained fibers was vesiculated and formed axo-dendritic synapses with the afferent auditory dendrites contacting the inner hair cells. A second type of ChAT-immunostained fibers seen in the inner spiral bundle was unvesiculated. Unstained vesiculated varicosities synapsing with the auditory dendrites were also seen in the inner spiral bundle. At the OHC level, ChAT immunostaining was found in nearly all the terminals synapsing with the OHCs. The finding of two types of ChAT-immunostained efferent synapses in the organ of Corti, i.e. axo-dendritic synapses in the inner spiral bundle and axo-somatic synapses with the OHCs, supports the hypothesis that both the lateral and the medial olivo-cochlear systems use acetylcholine as a neurotransmitter. The finding of numerous unstained synapses in the inner spiral bundle, and some below OHCs, together with previous data about putative cochlear neurotransmitters, suggests the possibility of additional non-cholinergic olivo-cochlear systems. It might soon appear useful to reclassify efferents according to the nature of the different neurotransmitters/co-transmitters found in the various efferent synapses of the organ of Corti.

NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area.

PubMed

Racca, C; Stephenson, F A; Streit, P; Roberts, J D; Somogyi, P

2000-04-01

Glutamate receptors activated by NMDA (NMDARs) or AMPA (AMPARs) are clustered on dendritic spines of pyramidal cells. Both the AMPAR-mediated postsynaptic responses and the synaptic AMPAR immunoreactivity show a large intersynapse variability. Postsynaptic responses mediated by NMDARs show less variability. To assess the variability in NMDAR content and the extent of their coexistence with AMPARs in Schaffer collateral-commissural synapses of adult rat CA1 pyramidal cells, electron microscopic immunogold localization of receptors has been used. Immunoreactivity of NMDARs was detected in virtually all synapses on spines, but AMPARs were undetectable, on average, in 12% of synapses. A proportion of synapses had a very high AMPAR content relative to the mean content, resulting in a distribution more skewed toward larger values than that of NMDARs. The variability of synaptic NMDAR content [coefficient of variation (CV), 0.64-0.70] was much lower than that of the AMPAR content (CV, 1.17-1.45). Unlike the AMPAR content, the NMDAR content showed only a weak correlation with synapse size. As reported previously for AMPARs, the immunoreactivity of NMDARs was also associated with the spine apparatus within spines. The results demonstrate that the majority of the synapses made by CA3 pyramidal cells onto spines of CA1 pyramids express both NMDARs and AMPARs, but with variable ratios. A less-variable NMDAR content is accompanied by a wide variability of AMPAR content, indicating that the regulation of expression of the two receptors is not closely linked. These findings support reports that fast excitatory transmission at some of these synapses is mediated by activation mainly of NMDARs.

Membrane Electromechanics at Hair-Cell Synapses

NASA Astrophysics Data System (ADS)

Brownell, W. E.; Farrell, B.; Raphael, R. M.

2003-02-01

Both outer hair cell electromotility and neurotransmission at the inner hair cell synapse are rapid mechanical events that are synchronized to the hair-cell receptor potential. We analyze whether the forces and potentials resulting from membrane flexoelectricity could affect synaptic vesicle fusion. The results suggest that the coupling of membrane curvature with membrane potential is of sufficient magnitude to influence neurotransmitter release.

Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein.

PubMed

Roy, Sougata; Huang, Hai; Liu, Songmei; Kornberg, Thomas B

2014-02-21

Decapentaplegic (Dpp), a Drosophila morphogen signaling protein, transfers directly at synapses made at sites of contact between cells that produce Dpp and cytonemes that extend from recipient cells. The Dpp that cytonemes receive moves together with activated receptors toward the recipient cell body in motile puncta. Genetic loss-of-function conditions for diaphanous, shibire, neuroglian, and capricious perturbed cytonemes by reducing their number or only the synapses they make with cells they target, and reduced cytoneme-mediated transport of Dpp and Dpp signaling. These experiments provide direct evidence that cells use cytonemes to exchange signaling proteins, that cytoneme-based exchange is essential for signaling and normal development, and that morphogen distribution and signaling can be contact-dependent, requiring cytoneme synapses.

Neuroligins/LRRTMs prevent activity- and Ca2+/calmodulin-dependent synapse elimination in cultured neurons

PubMed Central

Soler-Llavina, Gilberto J.; Fuccillo, Marc V.; Malenka, Robert C.; Südhof, Thomas C.

2011-01-01

Neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs) are postsynaptic cell adhesion molecules that bind to presynaptic neurexins. In this paper, we show that short hairpin ribonucleic acid–mediated knockdowns (KDs) of LRRTM1, LRRTM2, and/or NL-3, alone or together as double or triple KDs (TKDs) in cultured hippocampal neurons, did not decrease synapse numbers. In neurons cultured from NL-1 knockout mice, however, TKD of LRRTMs and NL-3 induced an ∼40% loss of excitatory but not inhibitory synapses. Strikingly, synapse loss triggered by the LRRTM/NL deficiency was abrogated by chronic blockade of synaptic activity as well as by chronic inhibition of Ca2+ influx or Ca2+/calmodulin (CaM) kinases. Furthermore, postsynaptic KD of CaM prevented synapse loss in a cell-autonomous manner, an effect that was reversed by CaM rescue. Our results suggest that two neurexin ligands, LRRTMs and NLs, act redundantly to maintain excitatory synapses and that synapse elimination caused by the absence of NLs and LRRTMs is promoted by synaptic activity and mediated by a postsynaptic Ca2+/CaM-dependent signaling pathway. PMID:21788371

Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse

PubMed Central

Lasserre, Rémi; Charrin, Stéphanie; Cuche, Céline; Danckaert, Anne; Thoulouze, Maria-Isabel; de Chaumont, Fabrice; Duong, Tarn; Perrault, Nathalie; Varin-Blank, Nadine; Olivo-Marin, Jean-Christophe; Etienne-Manneville, Sandrine; Arpin, Monique; Di Bartolo, Vincenzo; Alcover, Andrés

2010-01-01

T-cell receptor (TCR) signalling is triggered and tuned at immunological synapses by the generation of signalling complexes that associate into dynamic microclusters. Microcluster movement is necessary to tune TCR signalling, but the molecular mechanism involved remains poorly known. We show here that the membrane-microfilament linker ezrin has an important function in microcluster dynamics and in TCR signalling through its ability to set the microtubule network organization at the immunological synapse. Importantly, ezrin and microtubules are important to down-regulate signalling events leading to Erk1/2 activation. In addition, ezrin is required for appropriate NF-AT activation through p38 MAP kinase. Our data strongly support the notion that ezrin regulates immune synapse architecture and T-cell activation through its interaction with the scaffold protein Dlg1. These results uncover a crucial function for ezrin, Dlg1 and microtubules in the organization of the immune synapse and TCR signal down-regulation. Moreover, they underscore the importance of ezrin and Dlg1 in the regulation of NF-AT activation through p38. PMID:20551903

Prevention of Noise Damage to Cochlear Synapses

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0494 TITLE: Prevention of Noise Damage to Cochlear Synapses PRINCIPAL INVESTIGATOR: Steven Green CONTRACTING...to Cochlear Synapses 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0494 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Steven Green 5d. PROJECT...ABSTRACT Noise-induced synaptopathy is the result of excitotoxic trauma to cochlear synapses due to glutamate released from the hair cells. Excitotoxic

Centrosome docking at the immunological synapse is controlled by Lck signaling

PubMed Central

Tsun, Andy; Qureshi, Ihjaaz; Stinchcombe, Jane C.; Jenkins, Misty R.; de la Roche, Maike; Kleczkowska, Joanna; Zamoyska, Rose

2011-01-01

Docking of the centrosome at the plasma membrane directs lytic granules to the immunological synapse. To identify signals controlling centrosome docking at the synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression of the T cell receptor–activated tyrosine kinase Lck is ablated. In the absence of Lck, the centrosome is able to translocate around the nucleus toward the immunological synapse but is unable to dock at the plasma membrane. Lytic granules fail to polarize and release their contents, and target cells are not killed. In CTLs deficient in both Lck and the related tyrosine kinase Fyn, centrosome translocation is impaired, and the centrosome remains on the distal side of the nucleus relative to the synapse. These results show that repositioning of the centrosome in CTLs involves at least two distinct steps, with Lck signaling required for the centrosome to dock at the plasma membrane. PMID:21339332

Seizures beget seizures in temporal lobe epilepsies: the boomerang effects of newly formed aberrant kainatergic synapses.

PubMed

Ben-Ari, Yehezkel; Crepel, Valérie; Represa, Alfonso

2008-01-01

Do temporal lobe epilepsy (TLE) seizures in adults promote further seizures? Clinical and experimental data suggest that new synapses are formed after an initial episode of status epilepticus, however their contribution to the transformation of a naive network to an epileptogenic one has been debated. Recent experimental data show that newly formed aberrant excitatory synapses on the granule cells of the fascia dentate operate by means of kainate receptor-operated signals that are not present on naive granule cells. Therefore, genuine epileptic networks rely on signaling cascades that differentiate them from naive networks. Recurrent limbic seizures generated by the activation of kainate receptors and synapses in naive animals lead to the formation of novel synapses that facilitate the emergence of further seizures. This negative, vicious cycle illustrates the central role of reactive plasticity in neurological disorders.

Pre-neurodegeneration of mitral cells in the pcd mutant mouse is associated with DNA damage, transcriptional repression, and reorganization of nuclear speckles and Cajal bodies.

PubMed

Valero, Jorge; Berciano, Maria T; Weruaga, Eduardo; Lafarga, Miguel; Alonso, José R

2006-11-01

DNA damage and impairment of its repair underlie several neurodegenerative diseases. The Purkinje cell degeneration (pcd) mutation causes the loss of Nna1 expression and is associated with a selective and progressive degeneration of specific neuronal populations, including mitral cells in the olfactory bulb. Using an in situ transcription assay, molecular markers for both nuclear compartments and components of the DNA damage/repair pathway, and ultrastructural analysis, here we demonstrate that the pcd mutation induces the formation of DNA damage/repair foci in mitral cells. Furthermore, this effect is associated with transcriptional inhibition, heterochromatinization, nucleolar segregation and the reorganization of nuclear speckles of splicing factors and Cajal bodies. The most significant cytoplasmic alteration observed was a partial replacement of rough endoplasmic reticulum cisternae by a larger amount of free ribosomes, while other organelles were structurally preserved. The tools employed in this work may be of use for the early detection of predegenerative processes in neurodegenerative disorders and for validating rescue strategies.

Memory-Relevant Mushroom Body Output Synapses Are Cholinergic.

PubMed

Barnstedt, Oliver; Owald, David; Felsenberg, Johannes; Brain, Ruth; Moszynski, John-Paul; Talbot, Clifford B; Perrat, Paola N; Waddell, Scott

2016-03-16

Memories are stored in the fan-out fan-in neural architectures of the mammalian cerebellum and hippocampus and the insect mushroom bodies. However, whereas key plasticity occurs at glutamatergic synapses in mammals, the neurochemistry of the memory-storing mushroom body Kenyon cell output synapses is unknown. Here we demonstrate a role for acetylcholine (ACh) in Drosophila. Kenyon cells express the ACh-processing proteins ChAT and VAChT, and reducing their expression impairs learned olfactory-driven behavior. Local ACh application, or direct Kenyon cell activation, evokes activity in mushroom body output neurons (MBONs). MBON activation depends on VAChT expression in Kenyon cells and is blocked by ACh receptor antagonism. Furthermore, reducing nicotinic ACh receptor subunit expression in MBONs compromises odor-evoked activation and redirects odor-driven behavior. Lastly, peptidergic corelease enhances ACh-evoked responses in MBONs, suggesting an interaction between the fast- and slow-acting transmitters. Therefore, olfactory memories in Drosophila are likely stored as plasticity of cholinergic synapses. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

[Immunolocalization of choline acetyltransferase in 2 types of efferent synapses of the organ of Corti].

PubMed

Eybalin, M; Pujol, R

1985-01-01

The efferent (olivo-cochlear) innervation of the organ of Corti was studied using a monoclonal antibody against choline acetyltransferase (ChAT). In the inner spiral bundle (ISB), below the inner hair cells (IHCs), the anti-ChAT immunoreactivity was observed within unvesiculated fibers and vesiculated varicosities. Unreactive varicosities, at least as numerous as the immunoreactive ones, were also detected. Both types of vesiculated varicosities synapsed with the dendrites of the primary auditory neurons (afferent fibers) connected to the IHCs. At the outer hair cell (OHC) level, nearly all the vesiculated terminals making axo-somatic synapses with the OHCs were anti-ChAT immunoreactive. Only few terminals synapsing with the OHCs were unreactive. These findings allowed the differentiation of at least three types of efferent synapses in the organ of Corti. In the ISB, a first population of axo-dendritic synapses seems to be cholinergic whereas a second population might use another neurotransmitter. At the OHC level, our results support the hypothesis that acetylcholine is the neurotransmitter of nearly all the large axo-somatic synapses. The rare unreactive axo-somatic synapses could constitute a fourth and minor type of efferent synapse. Thus, it would be helpful to subclassify the efferent innervations of the organ of Corti according to their neurochemical nature. A re-evaluation of the whole body of available electrophysiological data would be also necessary, as until now, acetylcholine was considered as being the only efferent cochlear neurotransmitter.

High-frequency stimulation of the temporoammonic pathway induces input-specific long-term potentiation in subicular bursting cells.

PubMed

Fidzinski, Pawel; Wawra, Matthias; Bartsch, Julia; Heinemann, Uwe; Behr, Joachim

2012-01-09

The subiculum (Sub) as a part of the hippocampal formation is thought to play a functional role in learning and memory. In addition to its major input from CA1 pyramidal cells, the subiculum receives input from the entorhinal cortex (EC) via the temporoammonic pathway. Thus far, synaptic plasticity in the subiculum was mainly investigated at CA1-Sub synapses. According to their spiking pattern, pyramidal cells in the subiculum were classified as bursting cells and non-bursting cells. In the present study, we demonstrate that subicular bursting cells show input-specific forms of long-term potentiation (LTP). At CA1-Sub synapses, bursting cells have been shown to express a presynaptic NMDA receptor-dependent LTP that depends on the activation of a cAMP-PKA cascade (Wozny et al., Journal of Physiology 2008). In contrast, at EC-Sub synapses the induction of LTP in bursting cells shows a high induction-threshold and relies on the activation of postsynaptic NMDA receptors, postsynaptic depolarization and postsynaptic Ca(2+) influx. Each form of LTP is input-specific and fails to induce heterosynaptic plasticity. Taken together, our data suggest that distinct, input-specific mechanisms govern high frequency-induced LTP at subicular bursting cells' synapses. Copyright © 2011 Elsevier B.V. All rights reserved.

Receptor signaling clusters in the immune synapse(in eng)

DOE PAGES

Dustin, Michael L.; Groves, Jay T.

2012-02-23

Signaling processes between various immune cells involve large-scale spatial reorganization of receptors and signaling molecules within the cell-cell junction. These structures, now collectively referred to as immune synapses, interleave physical and mechanical processes with the cascades of chemical reactions that constitute signal transduction systems. Molecular level clustering, spatial exclusion, and long-range directed transport are all emerging as key regulatory mechanisms. The study of these processes is drawing researchers from physical sciences to join the effort and represents a rapidly growing branch of biophysical chemistry. Furthermore, recent advances in physical and quantitative analyses of signaling within the immune synapses are reviewedmore » here.« less

Receptor signaling clusters in the immune synapse (in eng)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dustin, Michael L.; Groves, Jay T.

2012-02-23

Signaling processes between various immune cells involve large-scale spatial reorganization of receptors and signaling molecules within the cell-cell junction. These structures, now collectively referred to as immune synapses, interleave physical and mechanical processes with the cascades of chemical reactions that constitute signal transduction systems. Molecular level clustering, spatial exclusion, and long-range directed transport are all emerging as key regulatory mechanisms. The study of these processes is drawing researchers from physical sciences to join the effort and represents a rapidly growing branch of biophysical chemistry. Furthermore, recent advances in physical and quantitative analyses of signaling within the immune synapses are reviewedmore » here.« less

Postsynaptic FMRP Promotes the Pruning of Cell-to-Cell Connections among Pyramidal Neurons in the L5A Neocortical Network

PubMed Central

Patel, Ankur B.; Loerwald, Kristofer W.; Huber, Kimberly M.

2014-01-01

Pruning of structural synapses occurs with development and learning. A deficit in pruning of cortical excitatory synapses and the resulting hyperconnectivity is hypothesized to underlie the etiology of fragile X syndrome (FXS) and related autistic disorders. However, clear evidence for pruning in neocortex and its impairment in FXS remains elusive. Using simultaneous recordings of pyramidal neurons in the layer 5A neocortical network of the wild-type (WT) mouse to observe cell-to-cell connections in isolation, we demonstrate here a specific form of “connection pruning.” Connection frequency among pyramidal neurons decreases between the third and fifth postnatal weeks, indicating a period of connection pruning. Over the same interval in the FXS model mouse, the Fmr1 knock-out (KO), connection frequency does not decrease. Therefore, connection frequency in the fifth week is higher in the Fmr1 KO compared with WT, indicating a state of hyperconnectivity. These alterations are due to postsynaptic deletion of Fmr1. At early ages (2 weeks), postsynaptic Fmr1 promoted the maturation of cell-to-cell connections, but not their number. These findings indicate that impaired connection pruning at later ages, and not an excess of connection formation, underlies the hyperconnectivity in the Fmr1 KO mouse. FMRP did not appear to regulate synapses individually, but instead regulated cell-to-cell connectivity in which groups of synapses mediating a single cell-to-cell connection are uniformly removed, retained, and matured. Although we do not link connection pruning directly to the pruning of structurally defined synapses, this study nevertheless provides an important model system for studying altered pruning in FXS. PMID:24573297

Postsynaptic FMRP promotes the pruning of cell-to-cell connections among pyramidal neurons in the L5A neocortical network.

PubMed

Patel, Ankur B; Loerwald, Kristofer W; Huber, Kimberly M; Gibson, Jay R

2014-02-26

Pruning of structural synapses occurs with development and learning. A deficit in pruning of cortical excitatory synapses and the resulting hyperconnectivity is hypothesized to underlie the etiology of fragile X syndrome (FXS) and related autistic disorders. However, clear evidence for pruning in neocortex and its impairment in FXS remains elusive. Using simultaneous recordings of pyramidal neurons in the layer 5A neocortical network of the wild-type (WT) mouse to observe cell-to-cell connections in isolation, we demonstrate here a specific form of "connection pruning." Connection frequency among pyramidal neurons decreases between the third and fifth postnatal weeks, indicating a period of connection pruning. Over the same interval in the FXS model mouse, the Fmr1 knock-out (KO), connection frequency does not decrease. Therefore, connection frequency in the fifth week is higher in the Fmr1 KO compared with WT, indicating a state of hyperconnectivity. These alterations are due to postsynaptic deletion of Fmr1. At early ages (2 weeks), postsynaptic Fmr1 promoted the maturation of cell-to-cell connections, but not their number. These findings indicate that impaired connection pruning at later ages, and not an excess of connection formation, underlies the hyperconnectivity in the Fmr1 KO mouse. FMRP did not appear to regulate synapses individually, but instead regulated cell-to-cell connectivity in which groups of synapses mediating a single cell-to-cell connection are uniformly removed, retained, and matured. Although we do not link connection pruning directly to the pruning of structurally defined synapses, this study nevertheless provides an important model system for studying altered pruning in FXS.

Functional asymmetry and plasticity of electrical synapses interconnecting neurons through a 36-state model of gap junction channel gating

PubMed Central

Kraujalis, Tadas; Maciunas, Kestutis

2017-01-01

We combined the Hodgkin–Huxley equations and a 36-state model of gap junction channel gating to simulate electrical signal transfer through electrical synapses. Differently from most previous studies, our model can account for dynamic modulation of junctional conductance during the spread of electrical signal between coupled neurons. The model of electrical synapse is based on electrical properties of the gap junction channel encompassing two fast and two slow gates triggered by the transjunctional voltage. We quantified the influence of a difference in input resistances of electrically coupled neurons and instantaneous conductance–voltage rectification of gap junctions on an asymmetry of cell-to-cell signaling. We demonstrated that such asymmetry strongly depends on junctional conductance and can lead to the unidirectional transfer of action potentials. The simulation results also revealed that voltage spikes, which develop between neighboring cells during the spread of action potentials, can induce a rapid decay of junctional conductance, thus demonstrating spiking activity-dependent short-term plasticity of electrical synapses. This conclusion was supported by experimental data obtained in HeLa cells transfected with connexin45, which is among connexin isoforms expressed in neurons. Moreover, the model allowed us to replicate the kinetics of junctional conductance under different levels of intracellular concentration of free magnesium ([Mg2+]i), which was experimentally recorded in cells expressing connexin36, a major neuronal connexin. We demonstrated that such [Mg2+]i-dependent long-term plasticity of the electrical synapse can be adequately reproduced through the changes of slow gate parameters of the 36-state model. This suggests that some types of chemical modulation of gap junctions can be executed through the underlying mechanisms of voltage gating. Overall, the developed model accounts for direction-dependent asymmetry, as well as for short- and long-term plasticity of electrical synapses. Our modeling results demonstrate that such complex behavior of the electrical synapse is important in shaping the response of coupled neurons. PMID:28384220

Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development.

PubMed

Li, Jun; Han, Wenyan; Pelkey, Kenneth A; Duan, Jingjing; Mao, Xia; Wang, Ya-Xian; Craig, Michael T; Dong, Lijin; Petralia, Ronald S; McBain, Chris J; Lu, Wei

2017-11-15

In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development. Published by Elsevier Inc.

Investigation of synapse formation and function in a glutamatergic-GABAergic two-neuron microcircuit.

PubMed

Chang, Chia-Ling; Trimbuch, Thorsten; Chao, Hsiao-Tuan; Jordan, Julia-Christine; Herman, Melissa A; Rosenmund, Christian

2014-01-15

Neural circuits are composed of mainly glutamatergic and GABAergic neurons, which communicate through synaptic connections. Many factors instruct the formation and function of these synapses; however, it is difficult to dissect the contribution of intrinsic cell programs from that of extrinsic environmental effects in an intact network. Here, we perform paired recordings from two-neuron microculture preparations of mouse hippocampal glutamatergic and GABAergic neurons to investigate how synaptic input and output of these two principal cells develop. In our reduced preparation, we found that glutamatergic neurons showed no change in synaptic output or input regardless of partner neuron cell type or neuronal activity level. In contrast, we found that glutamatergic input caused the GABAergic neuron to modify its output by way of an increase in synapse formation and a decrease in synaptic release efficiency. These findings are consistent with aspects of GABAergic synapse maturation observed in many brain regions. In addition, changes in GABAergic output are cell wide and not target-cell specific. We also found that glutamatergic neuronal activity determined the AMPA receptor properties of synapses on the partner GABAergic neuron. All modifications of GABAergic input and output required activity of the glutamatergic neuron. Because our system has reduced extrinsic factors, the changes we saw in the GABAergic neuron due to glutamatergic input may reflect initiation of maturation programs that underlie the formation and function of in vivo neural circuits.

Mechanisms underlying the temporal precision of sound coding at the inner hair cell ribbon synapse

PubMed Central

Moser, Tobias; Neef, Andreas; Khimich, Darina

2006-01-01

Our auditory system is capable of perceiving the azimuthal location of a low frequency sound source with a precision of a few degrees. This requires the auditory system to detect time differences in sound arrival between the two ears down to tens of microseconds. The detection of these interaural time differences relies on network computation by auditory brainstem neurons sharpening the temporal precision of the afferent signals. Nevertheless, the system requires the hair cell synapse to encode sound with the highest possible temporal acuity. In mammals, each auditory nerve fibre receives input from only one inner hair cell (IHC) synapse. Hence, this single synapse determines the temporal precision of the fibre. As if this was not enough of a challenge, the auditory system is also capable of maintaining such high temporal fidelity with acoustic signals that vary greatly in their intensity. Recent research has started to uncover the cellular basis of sound coding. Functional and structural descriptions of synaptic vesicle pools and estimates for the number of Ca2+ channels at the ribbon synapse have been obtained, as have insights into how the receptor potential couples to the release of synaptic vesicles. Here, we review current concepts about the mechanisms that control the timing of transmitter release in inner hair cells of the cochlea. PMID:16901948

Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team

NASA Technical Reports Server (NTRS)

Robertson, D.; Shannon, J. R.; Biaggioni, I.; Ertl, A. C.; Diedrich, A.; Carson, R.; Furlan, R.; Jacob, G.; Jordan, J.

2000-01-01

Orthostatic intolerance is a common problem for inbound space travelers. There is usually tachycardia on standing but blood pressure may be normal, low or, rarely, elevated. This condition is analogous to the orthostatic intolerance that occurs on Earth in individuals with orthostatic tachycardia, palpitations, mitral valve prolapse, and light-headedness. Our studies during the Neurolab mission indicated that sympathetic nerve traffic is raised in microgravity and that plasma norepinephrine is higher than baseline supine levels but lower than baseline upright levels. A subgroup of patients with familial orthostatic intolerance differ from inbound space travelers in that they have an alanine-to-to-proline mutation at amino acid position 457 in their norepinephrine transporter gene. This leads to poor clearance of norepinephrine from synapses, with consequent raised heart rate. Clinical features of these syndromes are presented.

Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell-mediated cytotoxicity.

PubMed

Tuli, Amit; Thiery, Jerome; James, Ashley M; Michelet, Xavier; Sharma, Mahak; Garg, Salil; Sanborn, Keri B; Orange, Jordan S; Lieberman, Judy; Brenner, Michael B

2013-12-01

Natural killer (NK) lymphocytes contain lysosome-related organelles (LROs), known as lytic granules, which upon formation of immune synapse with the target cell, polarize toward the immune synapse to deliver their contents to the target cell membrane. Here, we identify a small GTP-binding protein, ADP-ribosylation factor-like 8b (Arl8b), as a critical factor required for NK cell-mediated cytotoxicity. Our findings indicate that Arl8b drives the polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells. Using a glutathione S-transferase pull-down approach, we identify kinesin family member 5B (KIF5B; the heavy chain of kinesin-1) as an interaction partner of Arl8b from NK cell lysates. Previous studies showed that interaction between kinesin-1 and Arl8b is mediated by SifA and kinesin-interacting protein (SKIP) and the tripartite complex drives the anterograde movement of lysosomes. Silencing of both KIF5B and SKIP in NK cells, similar to Arl8b, led to failure of MTOC-lytic granule polarization to the immune synapse, suggesting that Arl8b and kinesin-1 together control this critical step in NK cell cytotoxicity.

Cytotoxic T cells use mechanical force to potentiate target cell killing

PubMed Central

Basu, Roshni; Whitlock, Benjamin M.; Husson, Julien; Le Floc’h, Audrey; Jin, Weiyang; Oyler-Yaniv, Alon; Dotiwala, Farokh; Giannone, Gregory; Hivroz, Claire; Biais, Nicolas; Lieberman, Judy; Kam, Lance C.; Huse, Morgan

2016-01-01

SUMMARY The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals. PMID:26924577

VLA-4 integrin concentrates at the peripheral supramolecular activation complex of the immune synapse and drives T helper 1 responses

NASA Astrophysics Data System (ADS)

Mittelbrunn, María; Molina, Ana; Escribese, María M.; Yáñez-Mó, María; Escudero, Ester; Ursa, Ángeles; Tejedor, Reyes; Mampaso, Francisco; Sánchez-Madrid, Francisco

2004-07-01

The integrin 41 (VLA-4) not only mediates the adhesion and transendothelial migration of leukocytes, but also provides costimulatory signals that contribute to the activation of T lymphocytes. However, the behavior of 41 during the formation of the immune synapse is currently unknown. Here, we show that 41 is recruited to both human and murine antigen-dependent immune synapses, when the antigen-presenting cell is a B lymphocyte or a dendritic cell, colocalizing with LFA-1 at the peripheral supramolecular activation complex. However, when conjugates are formed in the presence of anti-4 antibodies, VLA-4 colocalizes with the CD3- chain at the center of the synapse. In addition, antibody engagement of 4 integrin promotes polarization toward a T helper 1 (Th1) response in human in vitro models of CD4+ T cell differentiation and naïve T cell priming by dendritic cells. The in vivo administration of anti-4 integrin antibodies also induces an immune deviation to Th1 response that dampens a Th2-driven autoimmune nephritis in Brown Norway rats. These data reveal a regulatory role of 4 integrins on T lymphocyte-antigen presenting cell cognate immune interactions.

Imaging of Cell-Cell Communication in a Vertical Orientation Reveals High-Resolution Structure of Immunological Synapse and Novel PD-1 Dynamics

PubMed Central

Jang, Joon Hee; Huang, Yu; Zheng, Peilin; Jo, Myeong Chan; Bertolet, Grant; Qin, Lidong; Liu, Dongfang

2015-01-01

The immunological synapse (IS) is one of the most pivotal communication strategies in immune cells. Understanding the molecular basis of the IS provides critical information regarding how immune cells mount an effective immune response. Fluorescence microscopy provides a fundamental tool to study the IS. However, current imaging techniques for studying the IS cannot sufficiently achieve high resolution in real cell-cell conjugates. Here we present a new device that allows for high-resolution imaging of the IS with conventional confocal microscopy in a high-throughput manner. Combining micropits and single cell trap arrays, we have developed a new microfluidic platform that allows visualization of the IS in vertically “stacked” cells. Using this vertical cell pairing (VCP) system, we investigated the dynamics of the inhibitory synapse mediated by an inhibitory receptor, programed death protein-1 (PD-1) and the cytotoxic synapse at the single cell level. In addition to the technique innovation, we demonstrated novel biological findings by this VCP device, including novel distribution of F-actin and cytolytic granules at the IS, PD-1 microclusters in the NK IS, and kinetics of cytotoxicity. We propose that this high-throughput, cost-effective, easy-to-use VCP system, along with conventional imaging techniques, can be used to address a number of significant biological questions in a variety of disciplines. PMID:26123352

A Mathematical Model of the Olfactory Bulb for the Selective Adaptation Mechanism in the Rodent Olfactory System.

PubMed

Soh, Zu; Nishikawa, Shinya; Kurita, Yuichi; Takiguchi, Noboru; Tsuji, Toshio

2016-01-01

To predict the odor quality of an odorant mixture, the interaction between odorants must be taken into account. Previously, an experiment in which mice discriminated between odorant mixtures identified a selective adaptation mechanism in the olfactory system. This paper proposes an olfactory model for odorant mixtures that can account for selective adaptation in terms of neural activity. The proposed model uses the spatial activity pattern of the mitral layer obtained from model simulations to predict the perceptual similarity between odors. Measured glomerular activity patterns are used as input to the model. The neural interaction between mitral cells and granular cells is then simulated, and a dissimilarity index between odors is defined using the activity patterns of the mitral layer. An odor set composed of three odorants is used to test the ability of the model. Simulations are performed based on the odor discrimination experiment on mice. As a result, we observe that part of the neural activity in the glomerular layer is enhanced in the mitral layer, whereas another part is suppressed. We find that the dissimilarity index strongly correlates with the odor discrimination rate of mice: r = 0.88 (p = 0.019). We conclude that our model has the ability to predict the perceptual similarity of odorant mixtures. In addition, the model also accounts for selective adaptation via the odor discrimination rate, and the enhancement and inhibition in the mitral layer may be related to this selective adaptation.

Differential MicroRNA Expression Profile in Myxomatous Mitral Valve Prolapse and Fibroelastic Deficiency Valves

PubMed Central

Chen, Yei-Tsung; Wang, Juan; Wee, Abby S. Y.; Yong, Quek-Wei; Tay, Edgar Lik-Wui; Woo, Chin Cheng; Sorokin, Vitaly; Richards, Arthur Mark; Ling, Lieng-Hsi

2016-01-01

Myxomatous mitral valve prolapse (MMVP) and fibroelastic deficiency (FED) are two common variants of degenerative mitral valve disease (DMVD), which is a leading cause of mitral regurgitation worldwide. While pathohistological studies have revealed differences in extracellular matrix content in MMVP and FED, the molecular mechanisms underlying these two disease entities remain to be elucidated. By using surgically removed valvular specimens from MMVP and FED patients that were categorized on the basis of echocardiographic, clinical and operative findings, a cluster of microRNAs that expressed differentially were identified. The expressions of has-miR-500, -3174, -17, -1193, -646, -1273e, -4298, -203, -505, and -939 showed significant differences between MMVP and FED after applying Bonferroni correction (p < 0.002174). The possible involvement of microRNAs in the pathogenesis of DMVD were further suggested by the presences of in silico predicted target sites on a number of genes reported to be involved in extracellular matrix homeostasis and marker genes for cellular composition of mitral valves, including decorin (DCN), aggrecan (ACAN), fibromodulin (FMOD), α actin 2 (ACTA2), extracellular matrix protein 2 (ECM2), desmin (DES), endothelial cell specific molecule 1 (ESM1), and platelet/ endothelial cell adhesion molecule 1 (PECAM1), as well as inverse correlations of selected microRNA and mRNA expression in MMVP and FED groups. Our results provide evidence that distinct molecular mechanisms underlie MMVP and FED. Moreover, the microRNAs identified may be targets for the future development of diagnostic biomarkers and therapeutics. PMID:27213335

N-CADHERIN PRODOMAIN CLEAVAGE REGULATES SYNAPSE FORMATION IN VIVO

PubMed Central

Latefi, Nazlie S.; Pedraza, Liliana; Schohl, Anne; Li, Ziwei; Ruthazer, Edward S.

2009-01-01

Cadherins are initially synthesized bearing a prodomain that is thought to limit adhesion during early stages of biosynthesis. Functional cadherins lack this prodomain, raising the intriguing possibility that cells may utilize prodomain cleavage as a means to temporally or spatially regulate adhesion after delivery of cadherin to the cell surface. In support of this idea, immunostaining for the prodomain of zebrafish N-cadherin revealed enriched labeling at neuronal surfaces at the soma and along axonal processes. To determine whether post-translational cleavage of the prodomain affects synapse formation, we imaged Rohon-Beard cells in zebrafish embryos expressing GFP-tagged wild-type N-cadherin (NCAD-GFP) or a GFP-tagged N-cadherin mutant expressing an uncleavable prodomain (PRON-GFP) rendering it non-adhesive. NCAD-GFP accumulated at synaptic microdomains in a developmentally regulated manner, and its overexpression transiently accelerated synapse formation. PRON-GFP was much more diffusely distributed along the axon and its overexpression delayed synapse formation. Our results support the notion that N-cadherin serves to stabilize pre- to postsynaptic contacts early in synapse development and suggests that regulated cleavage of the N-cadherin prodomain may be a mechanism by which the kinetics of synaptogenesis are regulated. PMID:19365814

Qualitative and quantitative analysis of PMN/T-cell interactions by InFlow and super-resolution microscopy.

PubMed

Balta, Emre; Stopp, Julian; Castelletti, Laura; Kirchgessner, Henning; Samstag, Yvonne; Wabnitz, Guido H

2017-01-01

Neutrophils or polymorphonuclear cells (PMN) eliminate bacteria via phagocytosis and/or NETosis. Apart from these conventional roles, PMN also have immune-regulatory functions. They can transdifferentiate and upregulate MHCII as well as ligands for costimulatory receptors which enables them to behave as antigen presenting cells (APC). The initial step for activating T-cells is the formation of an immune synapse between T-cells and antigen-presenting cells. However, the immune synapse that develops at the PMN/T-cell contact zone is as yet hardly investigated due to the non-availability of methods for analysis of large number of PMN interactions. In order to overcome these obstacles, we introduce here a workflow to analyse the immune synapse of primary human PMN and T-cells using multispectral imaging flow cytometry (InFlow microscopy) and super-resolution microscopy. For that purpose, we used CD3 and CD66b as the lineage markers for T-cells and PMN, respectively. Thereafter, we applied and critically discussed various "masks" for identification of T-cell PMN interactions. Using this approach, we found that a small fraction of transdifferentiated PMN (CD66b + CD86 high ) formed stable PMN/T-cell conjugates. Interestingly, while both CD3 and CD66b accumulation in the immune synapse was dependent on the maturation state of the PMN, only CD3 accumulation was greatly enhanced by the presence of superantigen. The actin cytoskeleton was weakly rearranged at the PMN side on the immune synapse upon contact with a T-cell in the presence of superantigen. A more detailed analysis using super-resolution microscopy (structured-illumination microscopy, SIM) confirmed this finding. Together, we present an InFlow microscopy based approach for the large scale analysis of PMN/T-cell interactions and - combined with SIM - a possibility for an in-depth analysis of protein translocation at the site of interactions. Copyright © 2016 Elsevier Inc. All rights reserved.

A 3-synapse positive feedback loop regulates the excitability of an interneuron critical for sensitization in the leech.

PubMed

Crisp, Kevin M; Muller, Kenneth J

2006-03-29

Sensitization of reflexive shortening in the leech has been linked to serotonin (5-HT)-induced changes in the excitability of a single interneuron, the S cell. This neuron is necessary for sensitization and complete dishabituation of reflexive shortening, during which it contributes to the sensory-motor reflex. The S cell does not contain 5-HT, which is released primarily from the Retzius (R) cells, whose firing enhances S-cell excitability. Here, we show that the S cell excites the R cells, mainly via a fast disynaptic pathway in which the first synapse is the electrical junction between the S cell and the coupling interneurons, and the second synapse is a glutamatergic synapse of the coupling interneurons onto the R cells. The S cell-triggered excitatory postsynaptic potential in the R cell diminishes and nearly disappears in elevated concentrations of divalent cations because the coupling interneurons become inexcitable under these conditions. Serotonin released from the R cells feeds back on the S cell and increases its excitability by activating a 5-HT7-like receptor; 5-methoxytryptamine (5-MeOT; 10 microM) mimics the effects of 5-HT on S cell excitability, and effects of both 5-HT and 5-MeOT are blocked by pimozide (10 microM) and SB-269970 [(R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol] (5 microM). This feedback loop may be critical for the full expression of sensitization of reflexive shortening.

A 3-SYNAPSE POSITIVE FEEDBACK LOOP REGULATES THE EXCITABILITY OF AN INTERNEURON CRITICAL FOR SENSITIZATION IN THE LEECH

PubMed Central

Crisp, Kevin M.; Muller, Kenneth J.

2007-01-01

Sensitization of reflexive shortening in the leech has been linked to serotonin (5-HT)-induced changes in the excitability of a single interneuron, the S cell. This neuron is necessary for sensitization and complete dishabituation of reflexive shortening, during which it contributes to the sensory-motor reflex. The S cell does not contain 5-HT, which is released primarily from the Retzius (R) cells, whose firing enhances S-cell excitability. Here we show that the S cell excites the R cells, mainly via a fast disynaptic pathway in which the first synapse is the electrical junction between the S cell and the coupling interneurons, and the second synapse is a glutamatergic synapse of the coupling interneurons onto the R cells. The S cell-triggered excitatory postsynaptic potential in the R cell diminishes and nearly disappears in elevated concentrations of divalent cations because the coupling interneurons become inexcitable under these conditions. Serotonin released from the R cells feeds back upon the S cell and increases its excitability by activating a 5-HT7-like receptor; 5-methoxytryptamine (5-MeOT; 10 μM) mimics the effects of 5-HT on S cell excitability, and effects of both 5-HT and 5-MeOT are blocked by pimozide (10 μM) and SB-269970 (5 μM). This feedback loop may be critical for the full expression of sensitization of reflexive shortening. PMID:16571760

CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse.

PubMed

Masilamani, Madhan; Nguyen, Connie; Kabat, Juraj; Borrego, Francisco; Coligan, John E

2006-09-15

An adequate immune response is the result of the fine balance between activation and inhibitory signals. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94/NKG2A is an ITIM-containing inhibitory receptor expressed by NK cells and some CD8+ T cells that recognize HLA-E. We show that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94/NKG2A engagement leads to recruitment and activation of src homology 2 domain-bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrin-radixin-moesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrin-radixin-moesin phosphorylation. Thus, CD94/NKG2A prevents actin-dependent recruitment of raft-associated activation receptors complexes to the activating synapse. This was further substantiated by showing that inhibition of actin polymerization abolished lipid rafts exclusion at the iNKIS, whereas cholesterol depletion had no effect on actin disruption at the iNKIS. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.

Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

PubMed

Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

2017-05-10

Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells

PubMed Central

Pujol, Remy; Cunningham, Dale E.; Hailey, Dale W.; Prendergast, Andrew; Rubel, Edwin W.; Raible, David W.

2016-01-01

ABSTRACT Failure to form proper synapses in mechanosensory hair cells, the sensory cells responsible for hearing and balance, leads to deafness and balance disorders. Ribbons are electron-dense structures that tether synaptic vesicles to the presynaptic zone of mechanosensory hair cells where they are juxtaposed with the post-synaptic endings of afferent fibers. They are initially formed throughout the cytoplasm, and, as cells mature, ribbons translocate to the basolateral membrane of hair cells to form functional synapses. We have examined the effect of post-synaptic elements on ribbon formation and maintenance in the zebrafish lateral line system by observing mutants that lack hair cell innervation, wild-type larvae whose nerves have been transected and ribbons in regenerating hair cells. Our results demonstrate that innervation is not required for initial ribbon formation but suggest that it is crucial for regulating the number, size and localization of ribbons in maturing hair cells, and for ribbon maintenance at the mature synapse. PMID:27103160

Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells.

PubMed

Suli, Arminda; Pujol, Remy; Cunningham, Dale E; Hailey, Dale W; Prendergast, Andrew; Rubel, Edwin W; Raible, David W

2016-06-01

Failure to form proper synapses in mechanosensory hair cells, the sensory cells responsible for hearing and balance, leads to deafness and balance disorders. Ribbons are electron-dense structures that tether synaptic vesicles to the presynaptic zone of mechanosensory hair cells where they are juxtaposed with the post-synaptic endings of afferent fibers. They are initially formed throughout the cytoplasm, and, as cells mature, ribbons translocate to the basolateral membrane of hair cells to form functional synapses. We have examined the effect of post-synaptic elements on ribbon formation and maintenance in the zebrafish lateral line system by observing mutants that lack hair cell innervation, wild-type larvae whose nerves have been transected and ribbons in regenerating hair cells. Our results demonstrate that innervation is not required for initial ribbon formation but suggest that it is crucial for regulating the number, size and localization of ribbons in maturing hair cells, and for ribbon maintenance at the mature synapse. © 2016. Published by The Company of Biologists Ltd.

Actin Is Crucial for All Kinetically Distinguishable Forms of Endocytosis at Synapses.

PubMed

Wu, Xin-Sheng; Lee, Sung Hoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Wei-Dong; Wang, Dongsheng; Jin, Yinghui; Charnay, Patrick; Ervasti, James M; Wu, Ling-Gang

2016-12-07

Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using a knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, β- and γ-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. Published by Elsevier Inc.

Actin is crucial for all kinetically distinguishable forms of endocytosis at synapses

PubMed Central

Wu, Xin-Sheng; Lee, Sunghoon; Sheng, Jiansong; Zhang, Zhen; Zhao, Weidong; Wang, Dongsheng; Jin, Yinghui; Charnay, Patrick; Ervasti, James M.; Wu, Ling-Gang

2016-01-01

Summary Mechanical force is needed to mediate endocytosis. Whether actin, the most abundant force-generating molecule, is essential for endocytosis is highly controversial in mammalian cells, particularly synapses, likely due to the use of actin blockers, the efficiency and specificity of which are often unclear in the studied cell. Here we addressed this issue using knockout approach combined with measurements of membrane capacitance and fission pore conductance, imaging of vesicular protein endocytosis, and electron microscopy. We found that two actin isoforms, β- and γ-actin, are crucial for slow, rapid, bulk, and overshoot endocytosis at large calyx-type synapses, and for slow endocytosis and bulk endocytosis at small hippocampal synapses. Polymerized actin provides mechanical force to form endocytic pits. Actin also facilitates replenishment of the readily releasable vesicle pool, likely via endocytic clearance of active zones. We conclude that polymerized actin provides mechanical force essential for all kinetically distinguishable forms of endocytosis at synapses. PMID:27840001

Synapse fits neuron: joint reduction by model inversion.

PubMed

van der Scheer, H T; Doelman, A

2017-08-01

In this paper, we introduce a novel simplification method for dealing with physical systems that can be thought to consist of two subsystems connected in series, such as a neuron and a synapse. The aim of our method is to help find a simple, yet convincing model of the full cascade-connected system, assuming that a satisfactory model of one of the subsystems, e.g., the neuron, is already given. Our method allows us to validate a candidate model of the full cascade against data at a finer scale. In our main example, we apply our method to part of the squid's giant fiber system. We first postulate a simple, hypothetical model of cell-to-cell signaling based on the squid's escape response. Then, given a FitzHugh-type neuron model, we derive the verifiable model of the squid giant synapse that this hypothesis implies. We show that the derived synapse model accurately reproduces synaptic recordings, hence lending support to the postulated, simple model of cell-to-cell signaling, which thus, in turn, can be used as a basic building block for network models.

Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways

NASA Astrophysics Data System (ADS)

Chung, Won-Suk; Clarke, Laura E.; Wang, Gordon X.; Stafford, Benjamin K.; Sher, Alexander; Chakraborty, Chandrani; Joung, Julia; Foo, Lynette C.; Thompson, Andrew; Chen, Chinfei; Smith, Stephen J.; Barres, Ben A.

2013-12-01

To achieve its precise neural connectivity, the developing mammalian nervous system undergoes extensive activity-dependent synapse remodelling. Recently, microglial cells have been shown to be responsible for a portion of synaptic pruning, but the remaining mechanisms remain unknown. Here we report a new role for astrocytes in actively engulfing central nervous system synapses. This process helps to mediate synapse elimination, requires the MEGF10 and MERTK phagocytic pathways, and is strongly dependent on neuronal activity. Developing mice deficient in both astrocyte pathways fail to refine their retinogeniculate connections normally and retain excess functional synapses. Finally, we show that in the adult mouse brain, astrocytes continuously engulf both excitatory and inhibitory synapses. These studies reveal a novel role for astrocytes in mediating synapse elimination in the developing and adult brain, identify MEGF10 and MERTK as critical proteins in the synapse remodelling underlying neural circuit refinement, and have important implications for understanding learning and memory as well as neurological disease processes.

Integrating temperature with odor processing in the olfactory bulb.

PubMed

Kludt, Eugen; Okom, Camille; Brinkmann, Alexander; Schild, Detlev

2015-05-20

Temperature perception has long been classified as a somesthetic function solely. However, in recent years several studies brought evidence that temperature perception also takes place in the olfactory system of rodents. Temperature has been described as an effective stimulus for sensory neurons of the Grueneberg ganglion located at the entrance of the nose. Here, we investigate whether a neuronal trace of temperature stimulation can be observed in the glomeruli and mitral cells of the olfactory bulb, using calcium imaging and fast line-scanning microscopy. We show in the Xenopus tadpole system that the γ-glomerulus, which receives input from olfactory neurons, is highly sensitive to temperature drops at the olfactory epithelium. We observed that thermo-induced activity in the γ-glomerulus is conveyed to the mitral cells innervating this specific neuropil. Surprisingly, a substantial number of thermosensitive mitral cells were also chemosensitive. Moreover, we report another unique feature of the γ-glomerulus: it receives ipsilateral and contralateral afferents. The latter fibers pass through the contralateral bulb, cross the anterior commissure, and then run to the ipsilateral olfactory bulb, where they target the γ-glomerulus. Temperature drops at the contralateral olfactory epithelium also induced responses in the γ-glomerulus and in mitral cells. Temperature thus appears to be a relevant physiological input to the Xenopus olfactory system. Each olfactory bulb integrates and codes temperature signals originating from receptor neurons of the ipsilateral and contralateral nasal cavities. Finally, temperature and chemical information is processed in shared cellular networks. Copyright © 2015 the authors 0270-6474/15/357892-11$15.00/0.

From neural-based object recognition toward microelectronic eyes

NASA Technical Reports Server (NTRS)

Sheu, Bing J.; Bang, Sa Hyun

1994-01-01

Engineering neural network systems are best known for their abilities to adapt to the changing characteristics of the surrounding environment by adjusting system parameter values during the learning process. Rapid advances in analog current-mode design techniques have made possible the implementation of major neural network functions in custom VLSI chips. An electrically programmable analog synapse cell with large dynamic range can be realized in a compact silicon area. New designs of the synapse cells, neurons, and analog processor are presented. A synapse cell based on Gilbert multiplier structure can perform the linear multiplication for back-propagation networks. A double differential-pair synapse cell can perform the Gaussian function for radial-basis network. The synapse cells can be biased in the strong inversion region for high-speed operation or biased in the subthreshold region for low-power operation. The voltage gain of the sigmoid-function neurons is externally adjustable which greatly facilitates the search of optimal solutions in certain networks. Various building blocks can be intelligently connected to form useful industrial applications. Efficient data communication is a key system-level design issue for large-scale networks. We also present analog neural processors based on perceptron architecture and Hopfield network for communication applications. Biologically inspired neural networks have played an important role towards the creation of powerful intelligent machines. Accuracy, limitations, and prospects of analog current-mode design of the biologically inspired vision processing chips and cellular neural network chips are key design issues.

Altered Actin Centripetal Retrograde Flow in Physically Restricted Immunological Synapses

PubMed Central

Yu, Cheng-han; Wu, Hung-Jen; Kaizuka, Yoshihisa; Vale, Ronald D.; Groves, Jay T.

2010-01-01

Antigen recognition by T cells involves large scale spatial reorganization of numerous receptor, adhesion, and costimulatory proteins within the T cell-antigen presenting cell (APC) junction. The resulting patterns can be distinctive, and are collectively known as the immunological synapse. Dynamical assembly of cytoskeletal network is believed to play an important role in driving these assembly processes. In one experimental strategy, the APC is replaced with a synthetic supported membrane. An advantage of this configuration is that solid structures patterned onto the underlying substrate can guide immunological synapse assembly into altered patterns. Here, we use mobile anti-CD3ε on the spatial-partitioned supported bilayer to ligate and trigger T cell receptor (TCR) in live Jurkat T cells. Simultaneous tracking of both TCR clusters and GFP-actin speckles reveals their dynamic association and individual flow patterns. Actin retrograde flow directs the inward transport of TCR clusters. Flow-based particle tracking algorithms allow us to investigate the velocity distribution of actin flow field across the whole synapse, and centripetal velocity of actin flow decreases as it moves toward the center of synapse. Localized actin flow analysis reveals that, while there is no influence on actin motion from substrate patterns directly, velocity differences of actin are observed over physically trapped TCR clusters. Actin flow regains its velocity immediately after passing through confined TCR clusters. These observations are consistent with a dynamic and dissipative coupling between TCR clusters and viscoelastic actin network. PMID:20686692

The NG2 Protein Is Not Required for Glutamatergic Neuron-NG2 Cell Synaptic Signaling.

PubMed

Passlick, Stefan; Trotter, Jacqueline; Seifert, Gerald; Steinhäuser, Christian; Jabs, Ronald

2016-01-01

NG2 glial cells (as from now NG2 cells) are unique in receiving synaptic input from neurons. However, the components regulating formation and maintenance of these neuron-glia synapses remain elusive. The transmembrane protein NG2 has been considered a potential mediator of synapse formation and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) clustering, because it contains 2 extracellular Laminin G/Neurexin/Sex Hormone-Binding Globulin domains, which in neurons are crucial for formation of transsynaptic neuroligin-neurexin complexes. NG2 is connected via Glutamate Receptor-Interacting Protein with GluA2/3-containing AMPARs, thereby possibly mediating receptor clustering in glial postsynaptic density. To elucidate the role of NG2 in neuron-glia communication, we investigated glutamatergic synaptic transmission in juvenile and aged hippocampal NG2 cells of heterozygous and homozygous NG2 knockout mice. Neuron-NG2 cell synapses readily formed in the absence of NG2. Short-term plasticity, synaptic connectivity, postsynaptic AMPAR current kinetics, and density were not affected by NG2 deletion. During development, an NG2-independent acceleration of AMPAR current kinetics and decreased synaptic connectivity were observed. Our results indicate that the lack of NG2 does not interfere with genesis and basic properties of neuron-glia synapses. In addition, we demonstrate frequent expression of neuroligins 1-3 in juvenile and aged NG2 cells, suggesting a role of these molecules in synapse formation between NG2 glia and neurons. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The immune synapse clears and excludes molecules above a size threshold

PubMed Central

Cartwright, Adam N. R.; Griggs, Jeremy; Davis, Daniel M.

2014-01-01

Natural killer cells assess target cell health via interactions at the immune synapse (IS) that facilitates signal integration and directed secretion. Here we test whether the IS also functions as a gasket. Quantitative fluorescence microscopy of nanometer-scale dextrans within synapses formed by various effector-target cell conjugates reveal that molecules are excluded in a size-dependent manner at activating synapses. Dextran sized ≤4 nm move in and out of the IS, but access is significantly reduced (by >50%) for dextran sized 10–13 nm, and dextran ≥32 nm is almost entirely excluded. Depolymerization of F-actin abrogated exclusion. Unexpectedly, larger-sized dextrans are cleared as the IS assembles in a zipper-like manner. Monoclonal antibodies are also excluded from the IS but smaller single-domain antibodies are able to penetrate. Therefore, the IS can clear and exclude molecules above a size threshold, and drugs designed to target synaptic cytokines or cytotoxic proteins must fit these dimensions. PMID:25407222

Rolling blackout is required for bulk endocytosis in non-neuronal cells and neuronal synapses

PubMed Central

Vijayakrishnan, Niranjana; Woodruff, Elvin A.; Broadie, Kendal

2009-01-01

Summary Rolling blackout (RBO) is a Drosophila EFR3 integral membrane lipase. A conditional temperature-sensitive (TS) mutant (rbots) displays paralysis within minutes following a temperature shift from 25°C to 37°C, an impairment previously attributed solely to blocked synaptic-vesicle exocytosis. However, we found that rbots displays a strong synergistic interaction with the Syntaxin-1A TS allele syx3-69, recently shown to be a dominant positive mutant that increases Syntaxin-1A function. At neuromuscular synapses, rbots showed a strong defect in styryl-FM-dye (FM) endocytosis, and rbots;syx3-69 double mutants displayed a synergistic, more severe, endocytosis impairment. Similarly, central rbots synapses in primary brain culture showed severely defective FM endocytosis. Non-neuronal nephrocyte Garland cells showed the same endocytosis defect in tracer-uptake assays. Ultrastructurally, rbots displayed a specific defect in tracer uptake into endosomes in both neuronal and non-neuronal cells. At the rbots synapse, there was a total blockade of endosome formation via activity-dependent bulk endocytosis. Clathrin-mediated endocytosis was not affected; indeed, there was a significant increase in direct vesicle formation. Together, these results demonstrate that RBO is required for constitutive and/or bulk endocytosis and/or macropinocytosis in both neuronal and non-neuronal cells, and that, at the synapse, this mechanism is responsive to the rate of Syntaxin-1A-dependent exocytosis. PMID:19066280

Rolling blackout is required for bulk endocytosis in non-neuronal cells and neuronal synapses.

PubMed

Vijayakrishnan, Niranjana; Woodruff, Elvin A; Broadie, Kendal

2009-01-01

Rolling blackout (RBO) is a Drosophila EFR3 integral membrane lipase. A conditional temperature-sensitive (TS) mutant (rbo(ts)) displays paralysis within minutes following a temperature shift from 25 degrees C to 37 degrees C, an impairment previously attributed solely to blocked synaptic-vesicle exocytosis. However, we found that rbo(ts) displays a strong synergistic interaction with the Syntaxin-1A TS allele syx(3-69), recently shown to be a dominant positive mutant that increases Syntaxin-1A function. At neuromuscular synapses, rbo(ts) showed a strong defect in styryl-FM-dye (FM) endocytosis, and rbo(ts);syx(3-69) double mutants displayed a synergistic, more severe, endocytosis impairment. Similarly, central rbo(ts) synapses in primary brain culture showed severely defective FM endocytosis. Non-neuronal nephrocyte Garland cells showed the same endocytosis defect in tracer-uptake assays. Ultrastructurally, rbo(ts) displayed a specific defect in tracer uptake into endosomes in both neuronal and non-neuronal cells. At the rbo(ts) synapse, there was a total blockade of endosome formation via activity-dependent bulk endocytosis. Clathrin-mediated endocytosis was not affected; indeed, there was a significant increase in direct vesicle formation. Together, these results demonstrate that RBO is required for constitutive and/or bulk endocytosis and/or macropinocytosis in both neuronal and non-neuronal cells, and that, at the synapse, this mechanism is responsive to the rate of Syntaxin-1A-dependent exocytosis.

Exploring the retinal connectome

PubMed Central

Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Shaw, Margaret V.; Yang, Jia-Hui; DeMill, David; Lauritzen, James S.; Lin, Yanhua; Rapp, Kevin D.; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross

2011-01-01

Purpose A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. Methods We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Results Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices. Conclusions Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks. PMID:21311605

Exploring the retinal connectome.

PubMed

Anderson, James R; Jones, Bryan W; Watt, Carl B; Shaw, Margaret V; Yang, Jia-Hui; Demill, David; Lauritzen, James S; Lin, Yanhua; Rapp, Kevin D; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross; Marc, Robert E

2011-02-03

A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈ 2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive axonal veto synapses. (3) Chains of conventional synapses were very common, with intercalated glycinergic-GABAergic chains and very long chains associated with starburst amacrine cells. Glycinergic amacrine cells clearly play a major role in ON-OFF crossover inhibition. (4) Molecular and excitation mapping clearly segregates ultrastructurally defined bipolar cell groups into different response clusters. (5) Finally, low-resolution electron or optical imaging cannot reliably map synaptic connections by process geometry, as adjacency without synaptic contact is abundant in the retina. Only direct visualization of synapses and gap junctions suffices. Connectome assembly and analysis using conventional transmission electron microscopy is now practical for network discovery. Our surveys of volume RC1 demonstrate that previously studied systems such as the AII amacrine cell network involve more network motifs than previously known. The AII network, primarily considered a scotopic pathway, clearly derives ribbon synapse input from photopic ON and OFF cone bipolar cell networks and extensive photopic GABAergic amacrine cell inputs. Further, bipolar cells show extensive inputs and outputs along their axons, similar to multistratified nonmammalian bipolar cells. Physiologic evidence of significant ON-OFF channel crossover is strongly supported by our anatomic data, showing alternating glycine-to-GABA paths. Long chains of amacrine cell networks likely arise from homocellular GABAergic synapses between starburst amacrine cells. Deeper analysis of RC1 offers the opportunity for more complete descriptions of specific networks.

A spiking neural network model of self-organized pattern recognition in the early mammalian olfactory system.

PubMed

Kaplan, Bernhard A; Lansner, Anders

2014-01-01

Olfactory sensory information passes through several processing stages before an odor percept emerges. The question how the olfactory system learns to create odor representations linking those different levels and how it learns to connect and discriminate between them is largely unresolved. We present a large-scale network model with single and multi-compartmental Hodgkin-Huxley type model neurons representing olfactory receptor neurons (ORNs) in the epithelium, periglomerular cells, mitral/tufted cells and granule cells in the olfactory bulb (OB), and three types of cortical cells in the piriform cortex (PC). Odor patterns are calculated based on affinities between ORNs and odor stimuli derived from physico-chemical descriptors of behaviorally relevant real-world odorants. The properties of ORNs were tuned to show saturated response curves with increasing concentration as seen in experiments. On the level of the OB we explored the possibility of using a fuzzy concentration interval code, which was implemented through dendro-dendritic inhibition leading to winner-take-all like dynamics between mitral/tufted cells belonging to the same glomerulus. The connectivity from mitral/tufted cells to PC neurons was self-organized from a mutual information measure and by using a competitive Hebbian-Bayesian learning algorithm based on the response patterns of mitral/tufted cells to different odors yielding a distributed feed-forward projection to the PC. The PC was implemented as a modular attractor network with a recurrent connectivity that was likewise organized through Hebbian-Bayesian learning. We demonstrate the functionality of the model in a one-sniff-learning and recognition task on a set of 50 odorants. Furthermore, we study its robustness against noise on the receptor level and its ability to perform concentration invariant odor recognition. Moreover, we investigate the pattern completion capabilities of the system and rivalry dynamics for odor mixtures.

A spiking neural network model of self-organized pattern recognition in the early mammalian olfactory system

PubMed Central

Kaplan, Bernhard A.; Lansner, Anders

2014-01-01

Olfactory sensory information passes through several processing stages before an odor percept emerges. The question how the olfactory system learns to create odor representations linking those different levels and how it learns to connect and discriminate between them is largely unresolved. We present a large-scale network model with single and multi-compartmental Hodgkin–Huxley type model neurons representing olfactory receptor neurons (ORNs) in the epithelium, periglomerular cells, mitral/tufted cells and granule cells in the olfactory bulb (OB), and three types of cortical cells in the piriform cortex (PC). Odor patterns are calculated based on affinities between ORNs and odor stimuli derived from physico-chemical descriptors of behaviorally relevant real-world odorants. The properties of ORNs were tuned to show saturated response curves with increasing concentration as seen in experiments. On the level of the OB we explored the possibility of using a fuzzy concentration interval code, which was implemented through dendro-dendritic inhibition leading to winner-take-all like dynamics between mitral/tufted cells belonging to the same glomerulus. The connectivity from mitral/tufted cells to PC neurons was self-organized from a mutual information measure and by using a competitive Hebbian–Bayesian learning algorithm based on the response patterns of mitral/tufted cells to different odors yielding a distributed feed-forward projection to the PC. The PC was implemented as a modular attractor network with a recurrent connectivity that was likewise organized through Hebbian–Bayesian learning. We demonstrate the functionality of the model in a one-sniff-learning and recognition task on a set of 50 odorants. Furthermore, we study its robustness against noise on the receptor level and its ability to perform concentration invariant odor recognition. Moreover, we investigate the pattern completion capabilities of the system and rivalry dynamics for odor mixtures. PMID:24570657

Ca(2+) influx and neurotransmitter release at ribbon synapses.

PubMed

Cho, Soyoun; von Gersdorff, Henrique

2012-01-01

Ca(2+) influx through voltage-gated Ca(2+) channels triggers the release of neurotransmitters at presynaptic terminals. Some sensory receptor cells in the peripheral auditory and visual systems have specialized synapses that express an electron-dense organelle called a synaptic ribbon. Like conventional synapses, ribbon synapses exhibit SNARE-mediated exocytosis, clathrin-mediated endocytosis, and short-term plasticity. However, unlike non-ribbon synapses, voltage-gated L-type Ca(2+) channel opening at ribbon synapses triggers a form of multiquantal release that can be highly synchronous. Furthermore, ribbon synapses appear to be specialized for fast and high throughput exocytosis controlled by graded membrane potential changes. Here we will discuss some of the basic aspects of synaptic transmission at different types of ribbon synapses, and we will emphasize recent evidence that auditory and retinal ribbon synapses have marked differences. This will lead us to suggest that ribbon synapses are specialized for particular operating ranges and frequencies of stimulation. We propose that different types of ribbon synapses transfer diverse rates of sensory information by expressing a particular repertoire of critical components, and by placing them at precise and strategic locations, so that a continuous supply of primed vesicles and Ca(2+) influx leads to fast, accurate, and ongoing exocytosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse.

PubMed Central

Burroughs, Nigel John; Wülfing, Christoph

2002-01-01

Receptor-ligand couples in the cell-cell contact interface between a T cell and an antigen-presenting cell form distinct geometric patterns and undergo spatial rearrangement within the contact interface. Spatial segregation of the antigen and adhesion receptors occurs within seconds of contact, central aggregation of the antigen receptor then occurring over 1-5 min. This structure, called the immunological synapse, is becoming a paradigm for localized signaling. However, the mechanisms driving its formation, in particular spatial segregation, are currently not understood. With a reaction diffusion model incorporating thermodynamics, elasticity, and reaction kinetics, we examine the hypothesis that differing bond lengths (extracellular domain size) is the driving force behind molecular segregation. We derive two key conditions necessary for segregation: a thermodynamic criterion on the effective bond elasticity and a requirement for the seeding/nucleation of domains. Domains have a minimum length scale and will only spontaneously coalesce/aggregate if the contact area is small or the membrane relaxation distance large. Otherwise, differential attachment of receptors to the cytoskeleton is required for central aggregation. Our analysis indicates that differential bond lengths have a significant effect on synapse dynamics, i.e., there is a significant contribution to the free energy of the interaction, suggesting that segregation by differential bond length is important in cell-cell contact interfaces and the immunological synapse. PMID:12324401

Neto Auxiliary Protein Interactions Regulate Kainate and NMDA Receptor Subunit Localization at Mossy Fiber–CA3 Pyramidal Cell Synapses

PubMed Central

Wyeth, Megan S.; Pelkey, Kenneth A.; Petralia, Ronald S.; Salter, Michael W.; McInnes, Roderick R.

2014-01-01

Neto1 and Neto2 auxiliary subunits coassemble with NMDA receptors (NMDARs) and kainate receptors (KARs) to modulate their function. In the hippocampus, Neto1 enhances the amplitude and prolongs the kinetics of KAR-mediated currents at mossy fiber (MF)–CA3 pyramidal cell synapses. However, whether Neto1 trafficks KARs to synapses or simply alters channel properties is unresolved. Therefore, postembedding electron microscopy was performed to investigate the localization of GluK2/3 subunits at MF–CA3 synapses in Neto-null mice. Postsynaptic GluK2/3 Immunogold labeling was substantially reduced in Neto-null mice compared with wild types. Moreover, spontaneous KAR-mediated synaptic currents and metabotropic KAR signaling were absent in CA3 pyramidal cells of Neto-null mice. A similar loss of ionotropic and metabotropic KAR function was observed in Neto1, but not Neto2, single knock-out mice, specifically implicating Neto1 in regulating CA3 pyramidal cell KAR localization and function. Additional controversy pertains to the role of Neto proteins in modulating synaptic NMDARs. While Immunogold labeling for GluN2A at MF–CA3 synapses was comparable between wild-type and Neto-null mice, labeling for postsynaptic GluN2B was robustly increased in Neto-null mice. Accordingly, NMDAR-mediated currents at MF–CA3 synapses exhibited increased sensitivity to a GluN2B-selective antagonist in Neto1 knockouts relative to wild types. Thus, despite preservation of the overall MF–CA3 synaptic NMDAR-mediated current, loss of Neto1 alters NMDAR subunit composition. These results confirm that Neto protein interactions regulate synaptic localization of KAR and NMDAR subunits at MF–CA3 synapses, with implications for both ionotropic and metabotropic glutamatergic recruitment of the CA3 network. PMID:24403160

Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources.

PubMed

Omelchenko, N; Sesack, S R

2007-05-25

Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

Arf-like GTPase Arl8b regulates lytic granule polarization and natural killer cell–mediated cytotoxicity

PubMed Central

Tuli, Amit; Thiery, Jerome; James, Ashley M.; Michelet, Xavier; Sharma, Mahak; Garg, Salil; Sanborn, Keri B.; Orange, Jordan S.; Lieberman, Judy; Brenner, Michael B.

2013-01-01

Natural killer (NK) lymphocytes contain lysosome-related organelles (LROs), known as lytic granules, which upon formation of immune synapse with the target cell, polarize toward the immune synapse to deliver their contents to the target cell membrane. Here, we identify a small GTP-binding protein, ADP-ribosylation factor-like 8b (Arl8b), as a critical factor required for NK cell–mediated cytotoxicity. Our findings indicate that Arl8b drives the polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between effector NK lymphocytes and target cells. Using a glutathione S-transferase pull-down approach, we identify kinesin family member 5B (KIF5B; the heavy chain of kinesin-1) as an interaction partner of Arl8b from NK cell lysates. Previous studies showed that interaction between kinesin-1 and Arl8b is mediated by SifA and kinesin-interacting protein (SKIP) and the tripartite complex drives the anterograde movement of lysosomes. Silencing of both KIF5B and SKIP in NK cells, similar to Arl8b, led to failure of MTOC-lytic granule polarization to the immune synapse, suggesting that Arl8b and kinesin-1 together control this critical step in NK cell cytotoxicity. PMID:24088571

ON Cone Bipolar Cell Axonal Synapses in the OFF Inner Plexiform Layer of the Rabbit Retina

PubMed Central

Lauritzen, J. Scott; Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Mohammed, Shoeb; Hoang, John V.; Marc, Robert E.

2012-01-01

Analysis of the rabbit retinal connectome RC1 reveals that the division between the ON and OFF inner plexiform layer (IPL) is not structurally absolute. ON cone bipolar cells make non-canonical axonal synapses onto specific targets and receive amacrine cell synapses in the nominal OFF layer, creating novel motifs, including inhibitory crossover networks. Automated transmission electron microscope (ATEM) imaging, molecular tagging, tracing, and rendering of ≈ 400 bipolar cells reveals axonal ribbons in 36% of ON cone bipolar cells, throughout the OFF IPL. The targets include GABA-positive amacrine cells (γACs), glycine-positive amacrine cells (GACs) and ganglion cells. Most ON cone bipolar cell axonal contacts target GACs driven by OFF cone bipolar cells, forming new architectures for generating ON-OFF amacrine cells. Many of these ON-OFF GACs target ON cone bipolar cell axons, ON γACs and/or ON-OFF ganglion cells, representing widespread mechanisms for OFF to ON crossover inhibition. Other targets include OFF γACs presynaptic to OFF bipolar cells, forming γAC-mediated crossover motifs. ON cone bipolar cell axonal ribbons drive bistratified ON-OFF ganglion cells in the OFF layer and provide ON drive to polarity-appropriate targets such as bistratified diving ganglion cells (bsdGCs). The targeting precision of ON cone bipolar cell axonal synapses shows that this drive incidence is necessarily a joint distribution of cone bipolar cell axonal frequency and target cell trajectories through a given volume of the OFF layer. Such joint distribution sampling is likely common when targets are sparser than sources and when sources are coupled, as are ON cone bipolar cells. PMID:23042441

Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing.

PubMed

Basu, Roshni; Whitlock, Benjamin M; Husson, Julien; Le Floc'h, Audrey; Jin, Weiyang; Oyler-Yaniv, Alon; Dotiwala, Farokh; Giannone, Gregory; Hivroz, Claire; Biais, Nicolas; Lieberman, Judy; Kam, Lance C; Huse, Morgan

2016-03-24

The immunological synapse formed between a cytotoxic T lymphocyte (CTL) and an infected or transformed target cell is a physically active structure capable of exerting mechanical force. Here, we investigated whether synaptic forces promote the destruction of target cells. CTLs kill by secreting toxic proteases and the pore forming protein perforin into the synapse. Biophysical experiments revealed a striking correlation between the magnitude of force exertion across the synapse and the speed of perforin pore formation on the target cell, implying that force potentiates cytotoxicity by enhancing perforin activity. Consistent with this interpretation, we found that increasing target cell tension augmented pore formation by perforin and killing by CTLs. Our data also indicate that CTLs coordinate perforin release and force exertion in space and time. These results reveal an unappreciated physical dimension to lymphocyte function and demonstrate that cells use mechanical forces to control the activity of outgoing chemical signals. Copyright © 2016 Elsevier Inc. All rights reserved.

Ultrastructural analysis of chemical synapses and gap junctions between Drosophila brain neurons in culture.

PubMed

Oh, Hyun-Woo; Campusano, Jorge M; Hilgenberg, Lutz G W; Sun, Xicui; Smith, Martin A; O'Dowd, Diane K

2008-02-15

Dissociated cultures from many species have been important tools for exploring factors that regulate structure and function of central neuronal synapses. We have previously shown that cells harvested from brains of late stage Drosophila pupae can regenerate their processes in vitro. Electrophysiological recordings demonstrate the formation of functional synaptic connections as early as 3 days in vitro (DIV), but no information about synapse structure is available. Here, we report that antibodies against pre-synaptic proteins Synapsin and Bruchpilot result in punctate staining of regenerating neurites. Puncta density increases as neuritic plexuses develop over the first 4 DIV. Electron microscopy reveals that closely apposed neurites can form chemical synapses with both pre- and postsynaptic specializations characteristic of many inter-neuronal synapses in the adult brain. Chemical synapses in culture are restricted to neuritic processes and some neurite pairs form reciprocal synapses. GABAergic synapses have a significantly higher percentage of clear core versus granular vesicles than non-GABA synapses. Gap junction profiles, some adjacent to chemical synapses, suggest that neurons in culture can form purely electrical as well as mixed synapses, as they do in the brain. However, unlike adult brain, gap junctions in culture form between neuronal somata as well as neurites, suggesting soma ensheathing glia, largely absent in culture, regulate gap junction location in vivo. Thus pupal brain cultures, which support formation of interneuronal synapses with structural features similar to synapses in adult brain, are a useful model system for identifying intrinsic and extrinsic regulators of central synapse structure as well as function.

The Cerebellar Mossy Fiber Synapse as a Model for High-Frequency Transmission in the Mammalian CNS.

PubMed

Delvendahl, Igor; Hallermann, Stefan

2016-11-01

The speed of neuronal information processing depends on neuronal firing frequency. Here, we describe the evolutionary advantages and ubiquitous occurrence of high-frequency firing within the mammalian nervous system in general. The highest firing frequencies so far have been observed at the cerebellar mossy fiber to granule cell synapse. The mechanisms enabling high-frequency transmission at this synapse are reviewed and compared with other synapses. Finally, information coding of high-frequency signals at the mossy fiber synapse is discussed. The exceptionally high firing frequencies and amenability to high-resolution technical approaches both in vitro and in vivo establish the cerebellar mossy fiber synapse as an attractive model to investigate high-frequency signaling from the molecular up to the network level. Copyright © 2016 Elsevier Ltd. All rights reserved.

Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.

PubMed

Smith, Lindsey A; McMahon, Lori L

2018-02-01

Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density at two hippocampal synapses in male and ovariectomized female TgF344-AD rats and wildtype littermates, prior to reported behavioral deficits. Decreased basal synaptic transmission begins at medial perforant path-dentate granule cell (MPP-DGC) synapses prior to Schaffer-collateral-CA1 (CA3-CA1) synapses, in the absence of a change in paired-pulse ratio (PPR) or dendritic spine density. N-methyl-d-aspartate receptor (NMDAR)-dependent LTP magnitude is unaffected at CA3-CA1 synapses at 6, 9, and 12months of age, but is significantly increased at MPP-DGC synapses in TgF344-AD rats at 6months only. Sex differences were only observed at CA3-CA1 synapses where the decrease in basal transmission occurs at a younger age in males versus females. These are the first studies to define presymptomatic alterations in hippocampal synaptic transmission in the TgF344-AD rat model. The time course of altered synaptic transmission mimics the spread of pathology through hippocampus in human AD and provides support for this model as a valuable preclinical tool in elucidating pathological mechanisms of early synapse dysfunction in AD. Copyright © 2017. Published by Elsevier Inc.

T-cell synapse formation depends on antigen recognition but not CD3 interaction: studies with TCR:ζ, a candidate transgene for TCR gene therapy.

PubMed

Roszik, János; Sebestyén, Zsolt; Govers, Coen; Guri, Yakir; Szöor, Arpád; Pályi-Krekk, Zsuzsanna; Vereb, György; Nagy, Peter; Szöllosi, János; Debets, Reno

2011-05-01

T-cell receptors (TCRs) can be genetically modified to improve gene-engineered T-cell responses, a strategy considered critical for the success of clinical TCR gene therapy to treat cancers. TCR:ζ, which is a heterodimer of TCRα and β chains each coupled to complete human CD3ζ, overcomes issues of mis-pairing with endogenous TCR chains, shows high surface expression and mediates antigen-specific T-cell functions in vitro. In the current study, we further characterized TCR:ζ in gene-engineered T cells and assessed whether this receptor is able to interact with surface molecules and drive correct synapse formation in Jurkat T cells. The results showed that TCR:ζ mediates the formation of synaptic areas with antigen-positive target cells, interacts closely with CD8α and MHC class I (MHCI), and co-localizes with CD28, CD45 and lipid rafts, similar to WT TCR. TCR:ζ did not closely associate with endogenous CD3ε, despite its co-presence in immune synapses, and TCR:ζ showed enhanced synaptic accumulation in T cells negative for surface-expressed TCR molecules. Notably, synaptic TCR:ζ demonstrated lowered densities when compared with TCR in dual TCR T cells, a phenomenon that was related to both extracellular and intracellular CD3ζ domains present in the TCR:ζ molecule and responsible for enlarged synapse areas. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Train stimulation of parallel fibre to Purkinje cell inputs reveals two populations of synaptic responses with different receptor signatures

PubMed Central

Devi, Suma Priya Sudarsana; Howe, James R.

2016-01-01

Key points Purkinje cells of the cerebellum receive ∼180,000 parallel fibre synapses, which have often been viewed as a homogeneous synaptic population and studied using single action potentials.Many parallel fibre synapses might be silent, however, and granule cells in vivo fire in bursts. Here, we used trains of stimuli to study parallel fibre inputs to Purkinje cells in rat cerebellar slices.Analysis of train EPSCs revealed two synaptic components, phase 1 and 2. Phase 1 is initially large and saturates rapidly, whereas phase 2 is initially small and facilitates throughout the train. The two components have a heterogeneous distribution at dendritic sites and different pharmacological profiles.The differential sensitivity of phase 1 and phase 2 to inhibition by pentobarbital and NBQX mirrors the differential sensitivity of AMPA receptors associated with the transmembrane AMPA receptor regulatory protein, γ‐2, gating in the low‐ and high‐open probability modes, respectively. Abstract Cerebellar granule cells fire in bursts, and their parallel fibre axons (PFs) form ∼180,000 excitatory synapses onto the dendritic tree of a Purkinje cell. As many as 85% of these synapses have been proposed to be silent, but most are labelled for AMPA receptors. Here, we studied PF to Purkinje cell synapses using trains of 100 Hz stimulation in rat cerebellar slices. The PF train EPSC consisted of two components that were present in variable proportions at different dendritic sites: one, with large initial EPSC amplitude, saturated after three stimuli and dominated the early phase of the train EPSC; and the other, with small initial amplitude, increased steadily throughout the train of 10 stimuli and dominated the late phase of the train EPSC. The two phases also displayed different pharmacological profiles. Phase 2 was less sensitive to inhibition by NBQX but more sensitive to block by pentobarbital than phase 1. Comparison of synaptic results with fast glutamate applications to recombinant receptors suggests that the high‐open‐probability gating mode of AMPA receptors containing the auxiliary subunit transmembrane AMPA receptor regulatory protein γ‐2 makes a substantial contribution to phase 2. We argue that the two synaptic components arise from AMPA receptors with different functional signatures and synaptic distributions. Comparisons of voltage‐ and current‐clamp responses obtained from the same Purkinje cells indicate that phase 1 of the EPSC arises from synapses ideally suited to transmit short bursts of action potentials, whereas phase 2 is likely to arise from low‐release‐probability or ‘silent’ synapses that are recruited during longer bursts. PMID:27094216

Spontaneous Activity Drives Local Synaptic Plasticity In Vivo.

PubMed

Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, Christian

2015-07-15

Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in the mouse visual cortex in vivo. Analyzing activity changes across large populations of synapses revealed a simple and efficient local plasticity rule: synapses that exhibit low synchronicity with nearby neighbors (<12 μm) become depressed in their transmission frequency. Asynchronous electrical stimulation of individual synapses in hippocampal slices showed that this is due to a decrease in synaptic transmission efficiency. Accordingly, experimentally increasing local synchronicity, by stimulating synapses in response to spontaneous activity at neighboring synapses, stabilized synaptic transmission. Finally, blockade of the high-affinity proBDNF receptor p75(NTR) prevented the depression of asynchronously stimulated synapses. Thus, spontaneous activity drives local synaptic plasticity at individual synapses in an "out-of-sync, lose-your-link" fashion through proBDNF/p75(NTR) signaling to refine neuronal connectivity. VIDEO ABSTRACT. Copyright © 2015 Elsevier Inc. All rights reserved.

miRNA-431 Prevents Amyloid-β-Induced Synapse Loss in Neuronal Cell Culture Model of Alzheimer's Disease by Silencing Kremen1.

PubMed

Ross, Sean P; Baker, Kelly E; Fisher, Amanda; Hoff, Lee; Pak, Elena S; Murashov, Alexander K

2018-01-01

Synapse loss is well regarded as the underlying cause for the progressive decline of memory function over the course of Alzheimer's disease (AD) development. Recent observations suggest that the accumulation of the Wnt antagonist Dickkopf-1 (Dkk1) in the AD brain plays a critical role in triggering synaptic degeneration. Mechanistically, Dkk1 cooperates with Kremen1 (Krm1), its transmembrane receptor, to block the Wnt/β-catenin signaling pathway. Here, we show that silencing Krm1 with miR-431 prevents amyloid-β-mediated synapse loss in cortico-hippocampal cultures isolated from triple transgenic 3xTg-AD mice. Exposure to AβDDL (an amyloid-β derived diffusive ligand) or Dkk1 reduced the number of pre- and post-synaptic puncta in primary neuronal cultures, while treatment with miR-431 prevented synapse loss. In addition, treatment with miR-431 also prevented neurite degeneration. Our findings demonstrate that miR-431 protects synapses and neurites from Aβ-toxicity in an AD cell culture model and may be a promising therapeutic target.

Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation.

PubMed

Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano; Alviña, Karina; Zhang, Yuxiang; Dushko, Margaret; Ku, Taeyun; Zemoura, Khaled; Rich, David; Garcia-Dominguez, Dario; Hung, Matthew; Yelhekar, Tushar D; Sørensen, Andreas Toft; Xu, Weifeng; Chung, Kwanghun; Castillo, Pablo E; Lin, Yingxi

2018-03-07

Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Differentiating the aging of the mitral valve from human and canine myxomatous degeneration

PubMed Central

Connell, Patrick S.; Han, Richard I.; Grande-Allen, K. Jane

2012-01-01

During the course of both canine and human aging, the mitral valve remodels in generally predictable ways. The connection between these aging changes and the morbidity and mortality that accompany pathologic conditions has not been made clear. By exploring work that has investigated the specific valvular changes in both age and disease, with respect to the cells and the extracellular matrix found within the mitral valve, heretofore unexplored connections between age and myxomatous valve disease can be found. This review addresses several studies that have been conducted to explore such age and disease related changes in extracellular matrix, valvular endothelial and interstitial cells, and valve innervation, and also reviews attempts to correlate aging and myxomatous disease. Such connections can highlight avenues for future research and help provide insight as to when an individual diverts from an aging pattern into a diseased pathway. Recognizing these patterns and opportunities could result in earlier intervention and the hope of reduced morbidity and mortality for patients. PMID:22364720

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.

PubMed

Nguyen, Quynh-Anh; Horn, Meryl E; Nicoll, Roger A

2016-11-02

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.

Physiological and chemical analysis of neurotransmitter candidates at a fast excitatory synapse in the jellyfish Cyanea capillata (Cnidaria, Scyphozoa).

PubMed

Anderson, Peter A V; Trapido-Rosenthal, H G

2009-12-01

Motor nerve net (MNN) neurons in the jellyfish Cyanea capillata communicate with one another by way of fast, bidirectional excitatory chemical synapses. As is the case with almost all identified chemical synapses in cnidarians, the identity of the neurotransmitter at these synapses is unclear. MNN neurons are large enough for stable intracellular recordings. This, together with the fact that they can be exposed, providing unlimited access to them and to their synapses, prompted a study of the action of a variety of neurotransmitter candidates, including those typically associated with fast synapses in higher animals. Only the amino acids taurine and beta-alanine produced physiological responses consistent with those of the normal EPSP in these cells. Moreover, chemical analysis revealed that both taurine and beta-alanine are present in the neurons and released by depolarization. These various findings strongly suggest that either or both of these amino acids, or a closely related compound is the neurotransmitter at the fast chemical synapses between MNN neurons.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.

PubMed

Lu, Cecilia S; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-09-26

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

PubMed Central

Lu, Cecilia S.; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-01-01

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins. PMID:25135978

Comparative Anatomy of Phagocytic and Immunological Synapses

PubMed Central

Niedergang, Florence; Di Bartolo, Vincenzo; Alcover, Andrés

2016-01-01

The generation of phagocytic cups and immunological synapses are crucial events of the innate and adaptive immune responses, respectively. They are triggered by distinct immune receptors and performed by different cell types. However, growing experimental evidence shows that a very close series of molecular and cellular events control these two processes. Thus, the tight and dynamic interplay between receptor signaling, actin and microtubule cytoskeleton, and targeted vesicle traffic are all critical features to build functional phagosomes and immunological synapses. Interestingly, both phagocytic cups and immunological synapses display particular spatial and temporal patterns of receptors and signaling molecules, leading to the notion of “phagocytic synapse.” Here, we discuss both types of structures, their organization, and the mechanisms by which they are generated and regulated. PMID:26858721

A Model of In vitro Plasticity at the Parallel Fiber—Molecular Layer Interneuron Synapses

PubMed Central

Lennon, William; Yamazaki, Tadashi; Hecht-Nielsen, Robert

2015-01-01

Theoretical and computational models of the cerebellum typically focus on the role of parallel fiber (PF)—Purkinje cell (PKJ) synapses for learned behavior, but few emphasize the role of the molecular layer interneurons (MLIs)—the stellate and basket cells. A number of recent experimental results suggest the role of MLIs is more important than previous models put forth. We investigate learning at PF—MLI synapses and propose a mathematical model to describe plasticity at this synapse. We perform computer simulations with this form of learning using a spiking neuron model of the MLI and show that it reproduces six in vitro experimental results in addition to simulating four novel protocols. Further, we show how this plasticity model can predict the results of other experimental protocols that are not simulated. Finally, we hypothesize what the biological mechanisms are for changes in synaptic efficacy that embody the phenomenological model proposed here. PMID:26733856

The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapse

PubMed Central

Becker, Lars; Schnee, Michael E; Niwa, Mamiko; Sun, Willy; Maxeiner, Stephan; Talaei, Sara; Kachar, Bechara; Rutherford, Mark A

2018-01-01

The ribbon is the structural hallmark of cochlear inner hair cell (IHC) afferent synapses, yet its role in information transfer to spiral ganglion neurons (SGNs) remains unclear. We investigated the ribbon’s contribution to IHC synapse formation and function using KO mice lacking RIBEYE. Despite loss of the entire ribbon structure, synapses retained their spatiotemporal development and KO mice had a mild hearing deficit. IHCs of KO had fewer synaptic vesicles and reduced exocytosis in response to brief depolarization; a high stimulus level rescued exocytosis in KO. SGNs exhibited a lack of sustained excitatory postsynaptic currents (EPSCs). We observed larger postsynaptic glutamate receptor plaques, potentially compensating for the reduced EPSC rate in KO. Surprisingly, large-amplitude EPSCs were maintained in KO, while a small population of low-amplitude slower EPSCs was increased in number. The ribbon facilitates signal transduction at physiological stimulus levels by retaining a larger residency pool of synaptic vesicles. PMID:29328021

Relative Contributions of Specific Activity Histories and Spontaneous Processes to Size Remodeling of Glutamatergic Synapses

PubMed Central

Dvorkin, Roman; Ziv, Noam E.

2016-01-01

The idea that synaptic properties are defined by specific pre- and postsynaptic activity histories is one of the oldest and most influential tenets of contemporary neuroscience. Recent studies also indicate, however, that synaptic properties often change spontaneously, even in the absence of specific activity patterns or any activity whatsoever. What, then, are the relative contributions of activity history-dependent and activity history-independent processes to changes synapses undergo? To compare the relative contributions of these processes, we imaged, in spontaneously active networks of cortical neurons, glutamatergic synapses formed between the same axons and neurons or dendrites under the assumption that their similar activity histories should result in similar size changes over timescales of days. The size covariance of such commonly innervated (CI) synapses was then compared to that of synapses formed by different axons (non-CI synapses) that differed in their activity histories. We found that the size covariance of CI synapses was greater than that of non-CI synapses; yet overall size covariance of CI synapses was rather modest. Moreover, momentary and time-averaged sizes of CI synapses correlated rather poorly, in perfect agreement with published electron microscopy-based measurements of mouse cortex synapses. A conservative estimate suggested that ~40% of the observed size remodeling was attributable to specific activity histories, whereas ~10% and ~50% were attributable to cell-wide and spontaneous, synapse-autonomous processes, respectively. These findings demonstrate that histories of naturally occurring activity patterns can direct glutamatergic synapse remodeling but also suggest that the contributions of spontaneous, possibly stochastic, processes are at least as great. PMID:27776122

Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse.

PubMed

Reichardt, Peter; Dornbach, Bastian; Rong, Song; Beissert, Stefan; Gueler, Faikah; Loser, Karin; Gunzer, Matthias

2007-09-01

Naive B cells are ineffective antigen-presenting cells and are considered unable to activate naive T cells. However, antigen-specific contact of these cells leads to stable cell pairs that remain associated over hours in vivo. The physiologic role of such pairs has not been evaluated. We show here that antigen-specific conjugates between naive B cells and naive T cells display a mature immunologic synapse in the contact zone that is absent in T-cell-dendritic-cell (DC) pairs. B cells induce substantial proliferation but, contrary to DCs, no loss of L-selectin in T cells. Surprisingly, while DC-triggered T cells develop into normal effector cells, B-cell stimulation over 72 hours induces regulatory T cells inhibiting priming of fresh T cells in a contact-dependent manner in vitro. In vivo, the regulatory T cells home to lymph nodes where they potently suppress immune responses such as in cutaneous hypersensitivity and ectopic allogeneic heart transplant rejection. Our finding might help to explain old observations on tolerance induction by B cells, identify the mature immunologic synapse as a central functional module of this process, and suggest the use of naive B-cell-primed regulatory T cells, "bTregs," as a useful approach for therapeutic intervention in adverse adaptive immune responses.

Unidirectional signal propagation in primary neurons micropatterned at a single-cell resolution

NASA Astrophysics Data System (ADS)

Yamamoto, H.; Matsumura, R.; Takaoki, H.; Katsurabayashi, S.; Hirano-Iwata, A.; Niwano, M.

2016-07-01

The structure and connectivity of cultured neuronal networks can be controlled by using micropatterned surfaces. Here, we demonstrate that the direction of signal propagation can be precisely controlled at a single-cell resolution by growing primary neurons on micropatterns. To achieve this, we first examined the process by which axons develop and how synapses form in micropatterned primary neurons using immunocytochemistry. By aligning asymmetric micropatterns with a marginal gap, it was possible to pattern primary neurons with a directed polarization axis at the single-cell level. We then examined how synapses develop on micropatterned hippocampal neurons. Three types of micropatterns with different numbers of short paths for dendrite growth were compared. A normal development in synapse density was observed when micropatterns with three or more short paths were used. Finally, we performed double patch clamp recordings on micropatterned neurons to confirm that these synapses are indeed functional, and that the neuronal signal is transmitted unidirectionally in the intended orientation. This work provides a practical guideline for patterning single neurons to design functional neuronal networks in vitro with the direction of signal propagation being controlled.

Increased Cell-Intrinsic Excitability Induces Synaptic Changes in New Neurons in the Adult Dentate Gyrus That Require Npas4

PubMed Central

Sim, Shuyin; Antolin, Salome; Lin, Chia-Wei; Lin, Ying-Xi

2013-01-01

Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary. To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses. Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses. PMID:23637184

Three-dimensional imaging of HIV-1 virological synapses reveals membrane architectures involved in virus transmission.

PubMed

Do, Thao; Murphy, Gavin; Earl, Lesley A; Del Prete, Gregory Q; Grandinetti, Giovanna; Li, Guan-Han; Estes, Jacob D; Rao, Prashant; Trubey, Charles M; Thomas, James; Spector, Jeffrey; Bliss, Donald; Nath, Avindra; Lifson, Jeffrey D; Subramaniam, Sriram

2014-09-01

HIV transmission efficiency is greatly increased when viruses are transmitted at virological synapses formed between infected and uninfected cells. We have previously shown that virological synapses formed between HIV-pulsed mature dendritic cells (DCs) and uninfected T cells contain interdigitated membrane surfaces, with T cell filopodia extending toward virions sequestered deep inside invaginations formed on the DC membrane. To explore membrane structural changes relevant to HIV transmission across other types of intercellular conjugates, we used a combination of light and focused ion beam scanning electron microscopy (FIB-SEM) to determine the three-dimensional (3D) architectures of contact regions between HIV-1-infected CD4(+) T cells and either uninfected human CD4(+) T cells or human fetal astrocytes. We present evidence that in each case, membrane extensions that originate from the uninfected cells, either as membrane sheets or filopodial bridges, are present and may be involved in HIV transmission from infected to uninfected cells. We show that individual virions are distributed along the length of astrocyte filopodia, suggesting that virus transfer to the astrocytes is mediated, at least in part, by processes originating from the astrocyte itself. Mechanisms that selectively disrupt the polarization and formation of such membrane extensions could thus represent a possible target for reducing viral spread. Our findings lead to new insights into unique aspects of HIV transmission in the brain and at T cell-T cell synapses, which are thought to be a predominant mode of rapid HIV transmission early in the infection process. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Functional transformations of odor inputs in the mouse olfactory bulb.

PubMed

Adam, Yoav; Livneh, Yoav; Miyamichi, Kazunari; Groysman, Maya; Luo, Liqun; Mizrahi, Adi

2014-01-01

Sensory inputs from the nasal epithelium to the olfactory bulb (OB) are organized as a discrete map in the glomerular layer (GL). This map is then modulated by distinct types of local neurons and transmitted to higher brain areas via mitral and tufted cells. Little is known about the functional organization of the circuits downstream of glomeruli. We used in vivo two-photon calcium imaging for large scale functional mapping of distinct neuronal populations in the mouse OB, at single cell resolution. Specifically, we imaged odor responses of mitral cells (MCs), tufted cells (TCs) and glomerular interneurons (GL-INs). Mitral cells population activity was heterogeneous and only mildly correlated with the olfactory receptor neuron (ORN) inputs, supporting the view that discrete input maps undergo significant transformations at the output level of the OB. In contrast, population activity profiles of TCs were dense, and highly correlated with the odor inputs in both space and time. Glomerular interneurons were also highly correlated with the ORN inputs, but showed higher activation thresholds suggesting that these neurons are driven by strongly activated glomeruli. Temporally, upon persistent odor exposure, TCs quickly adapted. In contrast, both MCs and GL-INs showed diverse temporal response patterns, suggesting that GL-INs could contribute to the transformations MCs undergo at slow time scales. Our data suggest that sensory odor maps are transformed by TCs and MCs in different ways forming two distinct and parallel information streams.

Heterotypic gap junctions at glutamatergic mixed synapses are abundant in goldfish brain

PubMed Central

Rash, John E.; Kamasawa, Naomi; Vanderpool, Kimberly G.; Yasumura, Thomas; O'Brien, John; Nannapaneni, Srikant; Pereda, Alberto E.; Nagy, James I.

2014-01-01

Gap junctions provide for direct intercellular electrical and metabolic coupling. The abundance of gap junctions at “large myelinated club ending” synapses on Mauthner cells of the teleost brain provided a convenient model to correlate anatomical and physiological properties of electrical synapses. There, presynaptic action potentials were found to evoke short-latency electrical “pre-potentials” immediately preceding their accompanying glutamate-induced depolarizations, making these the first unambiguously identified “mixed” (i.e., chemical plus electrical) synapses in the vertebrate CNS. We recently showed that gap junctions at these synapses exhibit asymmetric electrical resistance (i.e., electrical rectification), which we correlated with total molecular asymmetry of connexin composition in their apposing gap junction hemiplaques, with Cx35 restricted to axon terminal hemiplaques and Cx34.7 restricted to apposing Mauthner cell plasma membranes. We now show that similarly heterotypic neuronal gap junctions are abundant throughout goldfish brain, with labeling exclusively for Cx35 in presynaptic hemiplaques and exclusively for Cx34.7 in postsynaptic hemiplaques. Moreover, the vast majority of these asymmetric gap junctions occur at glutamatergic axon terminals. The widespread distribution of heterotypic gap junctions at glutamatergic mixed synapses throughout goldfish brain and spinal cord implies that pre- vs. postsynaptic asymmetry at electrical synapses evolved early in the chordate lineage. We propose that the advantages of the molecular and functional asymmetry of connexins at electrical synapses that are so prominently expressed in the teleost CNS are unlikely to have been abandoned in higher vertebrates. However, to create asymmetric coupling in mammals, where most gap junctions are composed of Cx36 on both sides, would require some other mechanism, such as differential phosphorylation of connexins on opposite sides of the same gap junction or on asymmetric differences in the complement of their scaffolding and regulatory proteins. PMID:25451276

Mixed Electrical–Chemical Synapses in Adult Rat Hippocampus are Primarily Glutamatergic and Coupled by Connexin-36

PubMed Central

Hamzei-Sichani, Farid; Davidson, Kimberly G. V.; Yasumura, Thomas; Janssen, William G. M.; Wearne, Susan L.; Hof, Patrick R.; Traub, Roger D.; Gutiérrez, Rafael; Ottersen, Ole P.; Rash, John E.

2012-01-01

Dendrodendritic electrical signaling via gap junctions is now an accepted feature of neuronal communication in mammalian brain, whereas axodendritic and axosomatic gap junctions have rarely been described. We present ultrastructural, immunocytochemical, and dye-coupling evidence for “mixed” (electrical/chemical) synapses on both principal cells and interneurons in adult rat hippocampus. Thin-section electron microscopic images of small gap junction-like appositions were found at mossy fiber (MF) terminals on thorny excrescences of CA3 pyramidal neurons (CA3pyr), apparently forming glutamatergic mixed synapses. Lucifer Yellow injected into weakly fixed CA3pyr was detected in MF axons that contacted four injected CA3pyr, supporting gap junction-mediated coupling between those two types of principal cells. Freeze-fracture replica immunogold labeling revealed diverse sizes and morphologies of connexin-36-containing gap junctions throughout hippocampus. Of 20 immunogold-labeled gap junctions, seven were large (328–1140 connexons), three of which were consistent with electrical synapses between interneurons; but nine were at axon terminal synapses, three of which were immediately adjacent to distinctive glutamate receptor-containing postsynaptic densities, forming mixed glutamatergic synapses. Four others were adjacent to small clusters of immunogold-labeled 10-nm E-face intramembrane particles, apparently representing extrasynaptic glutamate receptor particles. Gap junctions also were on spines in stratum lucidum, stratum oriens, dentate gyrus, and hilus, on both interneurons and unidentified neurons. In addition, one putative GABAergic mixed synapse was found in thin-section images of a CA3pyr, but none were found by immunogold labeling, suggesting the rarity of GABAergic mixed synapses. Cx36-containing gap junctions throughout hippocampus suggest the possibility of reciprocal modulation of electrical and chemical signals in diverse hippocampal neurons. PMID:22615687

Minimally invasive right lateral thoracotomy without aortic cross-clamping: an attractive alternative to repeat sternotomy for reoperative mitral valve surgery.

PubMed

Umakanthan, Ramanan; Petracek, Michael R; Leacche, Marzia; Solenkova, Nataliya V; Eagle, Susan S; Thompson, Annemarie; Ahmad, Rashid M; Greelish, James P; Ball, Stephen K; Hoff, Steven J; Absi, Tarek S; Balaguer, Jorge M; Byrne, John G

2010-03-01

The study aim was to determine the safety and benefits of minimally invasive mitral valve surgery without aortic cross-clamping for mitral valve surgery after previous cardiac surgery. Between January 2006 and August 2008, a total of 90 consecutive patients (38 females, 52 males; mean age 66 +/- 9 years) underwent minimally invasive mitral valve surgery after having undergone previous cardiac surgery. Of these patients, 80 (89%) underwent mitral valve replacement and 10 (11%) mitral valve repair utilizing a small (5 cm) right lateral thoracotomy along the 4th or 5th intercostal space under fibrillatory arrest (mean temperature 28 +/- 2 degrees C). The predicted mortality, calculated using the Society of Thoracic Surgeons (STS) algorithm, was compared to the observed mortality. The mean ejection fraction was 45 +/- 13%, mean NYHA class 3 +/- 1, while 66 patients (73%) had previous coronary artery bypass grafting and 37 (41%) had previous valve surgery. Twenty-six patients (29%) underwent non-elective surgery. Cardiopulmonary bypass was instituted through axillary (n = 19), femoral (n = 70) or direct use aortic (n = 1) cannulation. Operative mortality was 2% (2/90), lower than the STS-predicted mortality of 7%. Three patients (3%) developed acute renal failure postoperatively, one patient (1%) required new-onset hemodialysis, and one (1%) developed postoperative stroke. No patients developed postoperative myocardial infarction. The mean postoperative packed red blood cell transfusion requirement at 48 h was 2 +/- 3 units. Minimally invasive right thoracotomy without aortic cross-clamping is an excellent alternative to conventional redo-sternotomy for reoperative mitral valve surgery. The present study confirmed that this technique is safe and effective in reducing operative mortality in high-risk patients undergoing reoperative cardiac surgery.

Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels.

PubMed

Nanou, Evanthia; Lee, Amy; Catterall, William A

2018-05-02

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remains uncertain. Here we show that regulation of voltage-gated calcium (Ca 2+ ) channel type 2.1 (Ca V 2.1) by neuronal Ca 2+ sensor (CaS) proteins controls synaptic plasticity and excitation/inhibition balance in a hippocampal circuit. Prevention of CaS protein regulation by introducing the IM-AA mutation in Ca V 2.1 channels in male and female mice impairs short-term synaptic facilitation at excitatory synapses of CA3 pyramidal neurons onto parvalbumin (PV)-expressing basket cells. In sharp contrast, the IM-AA mutation abolishes rapid synaptic depression in the inhibitory synapses of PV basket cells onto CA1 pyramidal neurons. These results show that CaS protein regulation of facilitation and inactivation of Ca V 2.1 channels controls the direction of short-term plasticity at these two synapses. Deletion of the CaS protein CaBP1/caldendrin also blocks rapid depression at PV-CA1 synapses, implicating its upregulation of inactivation of Ca V 2.1 channels in control of short-term synaptic plasticity at this inhibitory synapse. Studies of local-circuit function revealed reduced inhibition of CA1 pyramidal neurons by the disynaptic pathway from CA3 pyramidal cells via PV basket cells and greatly increased excitation/inhibition ratio of the direct excitatory input versus indirect inhibitory input from CA3 pyramidal neurons to CA1 pyramidal neurons. This striking defect in local-circuit function may contribute to the dramatic impairment of spatial learning and memory in IM-AA mice. SIGNIFICANCE STATEMENT Many forms of short-term synaptic plasticity in neuronal circuits rely on regulation of presynaptic voltage-gated Ca 2+ (Ca V ) channels. Regulation of Ca V 2.1 channels by neuronal calcium sensor (CaS) proteins controls short-term synaptic plasticity. Here we demonstrate a direct link between regulation of Ca V 2.1 channels and short-term synaptic plasticity in native hippocampal excitatory and inhibitory synapses. We also identify CaBP1/caldendrin as the calcium sensor interacting with Ca V 2.1 channels to mediate rapid synaptic depression in the inhibitory hippocampal synapses of parvalbumin-expressing basket cells to CA1 pyramidal cells. Disruption of this regulation causes altered short-term plasticity and impaired balance of hippocampal excitatory to inhibitory circuits. Copyright © 2018 the authors 0270-6474/18/384430-11$15.00/0.

Role of primary afferents in the developmental regulation of motor axon synapse numbers on Renshaw cells

PubMed Central

Siembab, Valerie C.; Gomez-Perez, Laura; Rotterman, Travis M.; Shneider, Neil A.; Alvarez, Francisco J.

2015-01-01

Motor function in mammalian species depends on the maturation of spinal circuits formed by a large variety of interneurons that regulate motoneuron firing and motor output. Interneuron activity is in turn modulated by the organization of their synaptic inputs, but the principles governing the development of specific synaptic architectures unique to each premotor interneuron are unknown. For example, Renshaw cells receive, at least in the neonate, convergent inputs from sensory afferents (likely Ia) and motor axons raising the question of whether they interact during Renshaw cell development. In other well-studied neurons, like Purkinje cells, heterosynaptic competition between inputs from different sources shapes synaptic organization. To examine the possibility that sensory afferents modulate synaptic maturation on developing Renshaw cells, we used three animal models in which afferent inputs in the ventral horn are dramatically reduced (Er81(−/−) knockout), weakened (Egr3(−/−) knockout) or strengthened (mlcNT3(+/−) transgenic). We demonstrate that increasing the strength of sensory inputs on Renshaw cells prevents their de-selection and reduces motor axon synaptic density and, in contrast, absent or diminished sensory afferent inputs correlate with increased densities of motor axons synapses. No effects were observed on other glutamatergic inputs. We conclude that the early strength of Ia synapses influences their maintenance or weakening during later development and that heterosynaptic influences from sensory synapses during early development regulates the density and organization of motor inputs on mature Renshaw cells. PMID:26660356

Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex

PubMed Central

Urban, Nathaniel N.

2012-01-01

Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here we demonstrate how the timescales associated with respiratory frequency, spike timing and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex. PMID:22553016

Multiple spike initiation zones in a neuron implicated in learning in the leech: a computational model.

PubMed

Crisp, Kevin M

2009-03-01

Sensitization of the defensive shortening reflex in the leech has been linked to a segmentally repeated tri-synaptic positive feedback loop. Serotonin from the R-cell enhances S-cell excitability, S-cell impulses cross an electrical synapse into the C-interneuron, and the C-interneuron excites the R-cell via a glutamatergic synapse. The C-interneuron has two unusual characteristics. First, impulses take longer to propagate from the S soma to the C soma than in the reverse direction. Second, impulses recorded from the electrically unexcitable C soma vary in amplitude when extracellular divalent cation concentrations are elevated, with smaller impulses failing to induce synaptic potentials in the R-cell. A compartmental, computational model was developed to test the sufficiency of multiple, independent spike initiation zones in the C-interneuron to explain these observations. The model displays asymmetric delays in impulse propagation across the S-C electrical synapse and graded impulse amplitudes in the C-interneuron in simulated high divalent cation concentrations.

Multiple functions of GABA A and GABA B receptors during pattern processing in the zebrafish olfactory bulb.

PubMed

Tabor, Rico; Yaksi, Emre; Friedrich, Rainer W

2008-07-01

gamma-Aminobutyric acid (GABA)ergic synapses are thought to play pivotal roles in the processing of activity patterns in the olfactory bulb (OB), but their functions have been difficult to study during odor responses in the intact system. We pharmacologically manipulated GABA(A) and GABA(B) receptors in the OB of zebrafish and analysed the effects on odor responses of the output neurons, the mitral cells (MCs), by electrophysiological recordings and temporally deconvolved two-photon Ca2+ imaging. The blockade of GABA(B) receptors enhanced presynaptic Ca2+ influx into afferent axon terminals, and changed the amplitude and time course of a subset of MC responses, indicating that GABA(B) receptors have a modulatory influence on OB output activity. The blockade of GABA(A) receptors induced epileptiform firing, enhanced excitatory responses and abolished fast oscillations in the local field potential. Moreover, the topological reorganization and decorrelation of MC activity patterns during the initial phase of the response was perturbed. These results indicate that GABA(A) receptor-containing circuits participate in the balance of excitation and inhibition, the regulation of total OB output activity, the synchronization of odor-dependent neuronal ensembles, and the reorganization of odor-encoding activity patterns. GABA(A) and GABA(B) receptors are therefore differentially involved in multiple functions of neuronal circuits in the OB.

Distribution and structure of efferent synapses in the chicken retina

PubMed Central

Lindstrom, SH; Nacsa, N; Blankenship, T; Fitzgerald, PG; Weller, C; Vaney, DI; Wilson, M

2012-01-01

The visual system of birds includes an efferent projection from a visual area, the isthmooptic nucleus in the midbrain, back to the retina. Using a combination of anterograde labeling of efferent fibers, reconstruction of dye-filled neurons, NADPH-diaphorase staining, and transmission electron microscopy we have examined the distribution of efferent fibers and their synaptic structures in the chicken retina. We show that efferent fibers terminate strictly within the ventral retina. In 2 completely mapped retinas, only 2 fibers from a total of 15,359 terminated in the dorsal retina. The major synapse made by each efferent fiber is with a single Efferent Target Amacrine Cell (TC). This synapse consists of 5-25 boutons of 2μm diameter, each with multiple active zones, pressed into the TC soma or synapsing with a basketwork of rudimentary TC dendrites in the inner nuclear layer (INL). This basketwork, which is sheathed by Muller cells processes, defines a private neuropil in the INL within which TCs were also seen to receive input from retinal neurons. In addition to the major synapse, efferent fibers typically produce several very thin processes that terminate nearby in single small boutons and for which the soma of a local amacrine cell is one of the likely postsynaptic partners. A minority of efferent fibers also give rise to a thicker process terminating in a strongly diaphorase positive ball about 5μm in diameter. PMID:19439107

Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system

PubMed Central

Finetti, Francesca; Patrussi, Laura; Masi, Giulia; Onnis, Anna; Galgano, Donatella; Lucherini, Orso Maria; Pazour, Gregory J.; Baldari, Cosima T.

2014-01-01

ABSTRACT T cell activation requires sustained signaling at the immune synapse, a specialized interface with the antigen-presenting cell (APC) that assembles following T cell antigen receptor (TCR) engagement by major histocompatibility complex (MHC)-bound peptide. Central to sustained signaling is the continuous recruitment of TCRs to the immune synapse. These TCRs are partly mobilized from an endosomal pool by polarized recycling. We have identified IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, as a central regulator of TCR recycling to the immune synapse. Here, we have investigated the interplay of IFT20 with the Rab GTPase network that controls recycling. We found that IFT20 forms a complex with Rab5 and the TCR on early endosomes. IFT20 knockdown (IFT20KD) resulted in a block in the recycling pathway, leading to a build-up of recycling TCRs in Rab5+ endosomes. Recycling of the transferrin receptor (TfR), but not of CXCR4, was disrupted by IFT20 deficiency. The IFT components IFT52 and IFT57 were found to act together with IFT20 to regulate TCR and TfR recycling. The results provide novel insights into the mechanisms that control TCR recycling and immune synapse assembly, and underscore the trafficking-related function of the IFT system beyond ciliogenesis. PMID:24554435

Biophysical Aspects of T Lymphocyte Activation at the Immune Synapse

PubMed Central

Hivroz, Claire; Saitakis, Michael

2016-01-01

T lymphocyte activation is a pivotal step of the adaptive immune response. It requires the recognition by T-cell receptors (TCR) of peptides presented in the context of major histocompatibility complex molecules (pMHC) present at the surface of antigen-presenting cells (APCs). T lymphocyte activation also involves engagement of costimulatory receptors and adhesion molecules recognizing ligands on the APC. Integration of these different signals requires the formation of a specialized dynamic structure: the immune synapse. While the biochemical and molecular aspects of this cell–cell communication have been extensively studied, its mechanical features have only recently been addressed. Yet, the immune synapse is also the place of exchange of mechanical signals. Receptors engaged on the T lymphocyte surface are submitted to many tensile and traction forces. These forces are generated by various phenomena: membrane undulation/protrusion/retraction, cell mobility or spreading, and dynamic remodeling of the actomyosin cytoskeleton inside the T lymphocyte. Moreover, the TCR can both induce force development, following triggering, and sense and convert forces into biochemical signals, as a bona fide mechanotransducer. Other costimulatory molecules, such as LFA-1, engaged during immune synapse formation, also display these features. Moreover, T lymphocytes themselves are mechanosensitive, since substrate stiffness can modulate their response. In this review, we will summarize recent studies from a biophysical perspective to explain how mechanical cues can affect T lymphocyte activation. We will particularly discuss how forces are generated during immune synapse formation; how these forces affect various aspects of T lymphocyte biology; and what are the key features of T lymphocyte response to stiffness. PMID:26913033

Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.

PubMed

Kallarackal, Angy J; Kvarta, Mark D; Cammarata, Erin; Jaberi, Leelah; Cai, Xiang; Bailey, Aileen M; Thompson, Scott M

2013-10-02

Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. We observed a decrease in AMPAR-mediated excitation at TA-CA1 synapses, but not Schaffer collateral-CA1 synapses, after CUS, with a corresponding layer-specific decrease in GluA1 expression. Both changes were reversed by chronic fluoxetine. CUS also disrupted long-term memory consolidation in the Morris water maze, a function of TA-CA1 synapses. The decreases in TA-CA1 AMPAR-mediated excitation and performance in the consolidation test were correlated positively with decreases in sucrose preference, a measure of anhedonia. We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses

PubMed Central

Nguyen, Quynh-Anh; Horn, Meryl E; Nicoll, Roger A

2016-01-01

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively. DOI: http://dx.doi.org/10.7554/eLife.19236.001 PMID:27805570

The Septate Junction Protein Caspr is Required for Structural Support and Retention of KCNQ4 at Calyceal Synapses of Vestibular Hair Cells

PubMed Central

Sousa, Aurea D.; Andrade, Leonardo R.; Salles, Felipe T.; Pillai, Anilkumar M.; Buttermore, Elizabeth; Bhat, Manzoor A.; Kachar, Bechara

2009-01-01

The afferent innervation contacting the type I hair cells of the vestibular sensory epithelia form distinct calyceal synapses. The apposed pre- and post-synaptic membranes at this large area of synaptic contact are kept at a remarkably regular distance. Here, we show by freeze-fracture electron microscopy that a patterned alignment of proteins at the calyceal membrane resembles a type of intercellular junction that is rare in vertebrates, the septate junction (SJ). We found that a core molecular component of SJs, Caspr, colocalizes with the K+ channel KCNQ4 at the post-synaptic membranes of these calyceal synapses. Immunolabeling and ultrastructural analyses of Caspr knockout mice reveal that, in the absence of Caspr, the separation between the membranes of the hair cells and the afferent neurons is conspicuously irregular and often increased by an order of magnitude. In these mutants, KCNQ4 fails to cluster at the post-synaptic membrane and appears diffused along the entire calyceal membrane. Our results indicate that a septate-like junction provides structural support to calyceal synaptic contact with the vestibular hair cell, and that Caspr is required for the recruitment or retention of KCNQ4 at these synapses. PMID:19279247

The Rab GTPase Rab8 as a shared regulator of ciliogenesis and immune synapse assembly: From a conserved pathway to diverse cellular structures.

PubMed

Patrussi, Laura; Baldari, Cosima T

2016-01-01

Rab GTPases, which form the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking. Among them, Rab8 is an essential participant in primary cilium formation. In a report recently published in the Journal of Cell Science, Finetti and colleagues identify Rab8 as a novel player in vesicular traffic in the non-ciliated T lymphocytes, which contributes to the assembly of the specialized signaling platform known as the immune synapse. By interacting with the v-SNARE VAMP-3, Rab8 is indeed responsible for the final docking/fusion step in T cell receptor (TCR) recycling to the immune synapse. A second important take-home message which comes to light from this work is that VAMP-3 also interacts with Rab8 at the base of the cilium in NIH-3T3 cells, where it regulates ciliary growth and targeting of Smoothened at the plasma membrane. Hence the data presented in this report, in addition to identifying Rab8 as a novel player in vesicular traffic to the immune synapse, reveal how both ciliated and non-ciliated cells take advantage of a conserved pathway to build highly specific cellular structures.

Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse

PubMed Central

Dhawale, Ashesh K.; Hagiwara, Akari; Bhalla, Upinder S.; Murthy, Venkatesh N.; Albeanu, Dinu F.

2011-01-01

Sensory inputs frequently converge on the brain in a spatially organized manner, often with overlapping inputs to multiple target neurons. Whether the responses of target neurons with common inputs become decorrelated depends on the contribution of local circuit interactions. We addressed this issue in the olfactory system using newly generated transgenic mice expressing channelrhodopsin-2 in all olfactory sensory neurons. By selectively stimulating individual glomeruli with light, we identified mitral/tufted (M/T) cells that receive common input (sister cells). Sister M/T cells had highly correlated responses to odors as measured by average spike rates, but their spike timing in relation to respiration was differentially altered. In contrast, non-sister M/T cells correlated poorly on both these measures. We suggest that sister M/T cells carry two different channels of information: average activity representing shared glomerular input, and phase-specific information that refines odor representations and is substantially independent for sister M/T cells. PMID:20953197

Long-term potentiation in hilar circuitry modulates gating by the dentate gyrus.

PubMed

Wright, Brandon J; Jackson, Meyer B

2014-07-16

The dentate gyrus serves as a gateway to the hippocampus, filtering and processing sensory inputs as an animal explores its environment. The hilus occupies a strategic position within the dentate gyrus from which it can play a pivotal role in these functions. Inputs from dentate granule cells converge on the hilus, and excitatory hilar mossy cells redistribute these signals back to granule cells to transform a pattern of cortical input into a new pattern of output to the hippocampal CA3 region. Using voltage-sensitive dye to image electrical activity in rat hippocampal slices, we explored how long-term potentiation (LTP) of different excitatory synapses modifies the flow of information. Theta burst stimulation of the perforant path potentiated responses throughout the molecular layer, but left responses in the CA3 region unchanged. By contrast, theta burst stimulation of the granule cell layer potentiated responses throughout the molecular layer, as well as in the CA3 region. Theta burst stimulation of the granule cell layer potentiated CA3 responses not only to granule cell layer stimulation but also to perforant path stimulation. Potentiation of responses in the CA3 region reflected NMDA receptor-dependent LTP of upstream synapses between granule cells and mossy cells, with no detectable contribution from NMDA receptor-independent LTP of local CA3 mossy fiber synapses. Potentiation of transmission to the CA3 region required LTP in both granule cell→mossy cell and mossy cell→granule cell synapses. This bidirectional plasticity enables hilar circuitry to regulate the flow of information through the dentate gyrus and on to the hippocampus. Copyright © 2014 the authors 0270-6474/14/349743-11$15.00/0.

Total Artificial Heart Implantation After Undifferentiated High-Grade Sarcoma Excision

PubMed Central

Kremer, Jamila; Farag, Mina; Arif, Rawa; Brcic, Andreas; Sabashnikov, Anton; Schmack, Bastian; Popov, Aron-Frederik; Karck, Matthias; Dohmen, Pascal M.; Ruhparwar, Arjang; Weymann, Alexander

2016-01-01

Background Total artificial heart (TAH) implantation in patients with aggressive tumor infiltration of the heart can be challenging. Case Report We report on a patient with a rare primary undifferentiated high-grade spindle cell sarcoma of the mitral valve and in the left atrium, first diagnosed in 2014. The referring center did a first resection in 2014. In the course of 17 months, computer tomography (CT) scan again showed massive invasion of the mitral valve and left atrium. Partial resection and mitral valve replacement was not an option. We did a subtotal heart excision with total artificial heart implantation. In this report we discuss complications, risk factors, and perioperative management of this patient. Conclusions Patients with aggressive tumors of the heart can be considered for TAH implantation. PMID:27803495

Total Artificial Heart Implantation After Undifferentiated High-Grade Sarcoma Excision.

PubMed

Kremer, Jamila; Farag, Mina; Arif, Rawa; Brcic, Andreas; Sabashnikov, Anton; Schmack, Bastian; Popov, Aron-Frederik; Karck, Matthias; Dohmen, Pascal M; Ruhparwar, Arjang; Weymann, Alexander

2016-11-02

BACKGROUND Total artificial heart (TAH) implantation in patients with aggressive tumor infiltration of the heart can be challenging. CASE REPORT We report on a patient with a rare primary undifferentiated high-grade spindle cell sarcoma of the mitral valve and in the left atrium, first diagnosed in 2014. The referring center did a first resection in 2014. In the course of 17 months, computer tomography (CT) scan again showed massive invasion of the mitral valve and left atrium. Partial resection and mitral valve replacement was not an option. We did a subtotal heart excision with total artificial heart implantation. In this report we discuss complications, risk factors, and perioperative management of this patient. CONCLUSIONS Patients with aggressive tumors of the heart can be considered for TAH implantation.

Accelerated intoxication of GABAergic synapses by botulinum neurotoxin A disinhibits stem cell-derived neuron networks prior to network silencing

PubMed Central

Beske, Phillip H.; Scheeler, Stephen M.; Adler, Michael; McNutt, Patrick M.

2015-01-01

Botulinum neurotoxins (BoNTs) are extremely potent toxins that specifically cleave SNARE proteins in peripheral synapses, preventing neurotransmitter release. Neuronal responses to BoNT intoxication are traditionally studied by quantifying SNARE protein cleavage in vitro or monitoring physiological paralysis in vivo. Consequently, the dynamic effects of intoxication on synaptic behaviors are not well-understood. We have reported that mouse embryonic stem cell-derived neurons (ESNs) are highly sensitive to BoNT based on molecular readouts of intoxication. Here we study the time-dependent changes in synapse- and network-level behaviors following addition of BoNT/A to spontaneously active networks of glutamatergic and GABAergic ESNs. Whole-cell patch-clamp recordings indicated that BoNT/A rapidly blocked synaptic neurotransmission, confirming that ESNs replicate the functional pathophysiology responsible for clinical botulism. Quantitation of spontaneous neurotransmission in pharmacologically isolated synapses revealed accelerated silencing of GABAergic synapses compared to glutamatergic synapses, which was consistent with the selective accumulation of cleaved SNAP-25 at GAD1+ pre-synaptic terminals at early timepoints. Different latencies of intoxication resulted in complex network responses to BoNT/A addition, involving rapid disinhibition of stochastic firing followed by network silencing. Synaptic activity was found to be highly sensitive to SNAP-25 cleavage, reflecting the functional consequences of the localized cleavage of the small subpopulation of SNAP-25 that is engaged in neurotransmitter release in the nerve terminal. Collectively these findings illustrate that use of synaptic function assays in networked neurons cultures offers a novel and highly sensitive approach for mechanistic studies of toxin:neuron interactions and synaptic responses to BoNT. PMID:25954159

A correlative and quantitative imaging approach enabling characterization of primary cell-cell communication: Case of human CD4+ T cell-macrophage immunological synapses.

PubMed

Kasprowicz, Richard; Rand, Emma; O'Toole, Peter J; Signoret, Nathalie

2018-05-22

Cell-to-cell communication engages signaling and spatiotemporal reorganization events driven by highly context-dependent and dynamic intercellular interactions, which are difficult to capture within heterogeneous primary cell cultures. Here, we present a straightforward correlative imaging approach utilizing commonly available instrumentation to sample large numbers of cell-cell interaction events, allowing qualitative and quantitative characterization of rare functioning cell-conjugates based on calcium signals. We applied this approach to examine a previously uncharacterized immunological synapse, investigating autologous human blood CD4 + T cells and monocyte-derived macrophages (MDMs) forming functional conjugates in vitro. Populations of signaling conjugates were visualized, tracked and analyzed by combining live imaging, calcium recording and multivariate statistical analysis. Correlative immunofluorescence was added to quantify endogenous molecular recruitments at the cell-cell junction. By analyzing a large number of rare conjugates, we were able to define calcium signatures associated with different states of CD4 + T cell-MDM interactions. Quantitative image analysis of immunostained conjugates detected the propensity of endogenous T cell surface markers and intracellular organelles to polarize towards cell-cell junctions with high and sustained calcium signaling profiles, hence defining immunological synapses. Overall, we developed a broadly applicable approach enabling detailed single cell- and population-based investigations of rare cell-cell communication events with primary cells.

Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

PubMed

Booker, Sam A; Campbell, Graham R; Mysiak, Karolina S; Brophy, Peter J; Kind, Peter C; Mahad, Don J; Wyllie, David J A

2017-03-15

Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function. Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV-deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy-fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short-term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

The CNS connectome of a tadpole larva of Ciona intestinalis (L.) highlights sidedness in the brain of a chordate sibling.

PubMed

Ryan, Kerrianne; Lu, Zhiyuan; Meinertzhagen, Ian A

2016-12-06

Left-right asymmetries in brains are usually minor or cryptic. We report brain asymmetries in the tiny, dorsal tubular nervous system of the ascidian tadpole larva, Ciona intestinalis . Chordate in body plan and development, the larva provides an outstanding example of brain asymmetry. Although early neural development is well studied, detailed cellular organization of the swimming larva's CNS remains unreported. Using serial-section EM we document the synaptic connectome of the larva's 177 CNS neurons. These formed 6618 synapses including 1772 neuromuscular junctions, augmented by 1206 gap junctions. Neurons are unipolar with at most a single dendrite, and few synapses. Some synapses are unpolarised, others form reciprocal or serial motifs; 922 were polyadic. Axo-axonal synapses predominate. Most neurons have ciliary organelles, and many features lack structural specialization. Despite equal cell numbers on both sides, neuron identities and pathways differ left/right. Brain vesicle asymmetries include a right ocellus and left coronet cells.

Multiple cell adhesion molecules shaping a complex nicotinic synapse on neurons.

PubMed

Triana-Baltzer, Gallen B; Liu, Zhaoping; Gounko, Natalia V; Berg, Darwin K

2008-09-01

Neuroligin, SynCAM, and L1-CAM are cell adhesion molecules with synaptogenic roles in glutamatergic pathways. We show here that SynCAM is expressed in the chick ciliary ganglion, embedded in a nicotinic pathway, and, as shown previously for neuroligin and L1-CAM, acts transcellularly to promote synaptic maturation on the neurons in culture. Moreover, we show that electroporation of chick embryos with dominant negative constructs disrupting any of the three molecules in vivo reduces the total amount of presynaptic SV2 overlaying the neurons expressing the constructs. Only disruption of L1-CAM and neuroligin, however, reduces the number of SV2 puncta specifically overlaying nicotinic receptor clusters. Disrupting L1-CAM and neuroligin together produces no additional decrement, indicating that they act on the same subset of synapses. SynCAM may affect synaptic maturation rather than synapse formation. The results indicate that individual neurons can express multiple synaptogenic molecules with different effects on the same class of nicotinic synapses.

The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.

PubMed

Martin, E Anne; Muralidhar, Shruti; Wang, Zhirong; Cervantes, Diégo Cordero; Basu, Raunak; Taylor, Matthew R; Hunter, Jennifer; Cutforth, Tyler; Wilke, Scott A; Ghosh, Anirvan; Williams, Megan E

2015-11-17

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.

Evidence for Alzheimer's disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons.

PubMed

Neuman, Krystina M; Molina-Campos, Elizabeth; Musial, Timothy F; Price, Andrea L; Oh, Kwang-Jin; Wolke, Malerie L; Buss, Eric W; Scheff, Stephen W; Mufson, Elliott J; Nicholson, Daniel A

2015-11-01

Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.

Edwardsiella tarda Endocarditis Confirmed by Indium-111 White Blood Cell Scan: An Unusual Pathogen and Diagnostic Modality.

PubMed

Litton, Kayleigh M; Rogers, Bret A

2016-01-01

Edwardsiella tarda is a freshwater marine member of the family Enterobacteriaceae which often colonizes fish, lizards, snakes, and turtles but is an infrequent human pathogen. Indium-111- ((111)In-) labeled white blood cell (WBC) scintigraphy is an imaging modality which has a wide range of reported sensitivity and specificity (from 60 to 100% and from 68 to 92%, resp.) for diagnosing acute and chronic infection. We describe a case of suspected E. tarda prosthetic aortic valve and mitral valve endocarditis with probable vegetations and new mitral regurgitation on transthoracic and transesophageal echocardiograms which was supported with the use of (111)In-labeled WBC scintigraphy.

Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

PubMed Central

Iball, Jonathan; Ali, Afia B.

2011-01-01

Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization. PMID:22125513

Prenatal and Early Postnatal Odorant Exposure Heightens Odor-Evoked Mitral Cell Responses in the Mouse Olfactory Bulb

PubMed Central

2017-01-01

Abstract Early sensory experience shapes the anatomy and function of sensory circuits. In the mouse olfactory bulb (OB), prenatal and early postnatal odorant exposure through odorized food (food/odorant pairing) not only increases the volume of activated glomeruli but also increases the number of mitral and tufted cells (M/TCs) connected to activated glomeruli. Given the importance of M/TCs in OB output and in mediating lateral inhibitory networks, increasing the number of M/TCs connected to a single glomerulus may significantly change odorant representation by increasing the total output of that glomerulus and/or by increasing the strength of lateral inhibition mediated by cells connected to the affected glomerulus. Here, we seek to understand the functional impact of this long-term odorant exposure paradigm on the population activity of mitral cells (MCs). We use viral expression of GCaMP6s to examine odor-evoked responses of MCs following prenatal and early postnatal odorant exposure to two dissimilar odorants, methyl salicylate (MS) and hexanal, which are both strong activators of glomeruli on the dorsal OB surface. Previous work suggests that odor familiarity may decrease odor-evoked MC response in rodents. However, we find that early food-based odorant exposure significantly changes MC responses in an unexpected way, resulting in broad increases in the amplitude, number, and reliability of excitatory MC responses across the dorsal OB. PMID:28955723

The organization of plasticity in the cerebellar cortex: from synapses to control.

PubMed

D'Angelo, Egidio

2014-01-01

The cerebellum is thought to play a critical role in procedural learning, but the relationship between this function and the underlying cellular and synaptic mechanisms remains largely speculative. At present, at least nine forms of long-term synaptic and nonsynaptic plasticity (some of which are bidirectional) have been reported in the cerebellar cortex and deep cerebellar nuclei. These include long-term potentiation (LTP) and long-term depression at the mossy fiber-granule cell synapse, at the synapses formed by parallel fibers, climbing fibers, and molecular layer interneurons on Purkinje cells, and at the synapses formed by mossy fibers and Purkinje cells on deep cerebellar nuclear cells, as well as LTP of intrinsic excitability in granule cells, Purkinje cells, and deep cerebellar nuclear cells. It is suggested that the complex properties of cerebellar learning would emerge from the distribution of plasticity in the network and from its dynamic remodeling during the different phases of learning. Intrinsic and extrinsic factors may hold the key to explain how the different forms of plasticity cooperate to select specific transmission channels and to regulate the signal-to-noise ratio through the cerebellar cortex. These factors include regulation of neuronal excitation by local inhibitory networks, engagement of specific molecular mechanisms by spike bursts and theta-frequency oscillations, and gating by external neuromodulators. Therefore, a new and more complex view of cerebellar plasticity is emerging with respect to that predicted by the original "Motor Learning Theory," opening issues that will require experimental and computational testing. © 2014 Elsevier B.V. All rights reserved.

Shockwaves Cause Synaptic Degeneration in Cultured Neurons

DTIC Science & Technology

2009-11-02

constructed of delrin. A piezoresistive pressure sensor (Endevco Model 8530C) was mounted flush with the plate, coaxial with the center of the gene gun ...biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in vitro, and after a 24-48...neurons, we used a biolostic gene gun to deliver shockwaves to cultured hippocampal or cortical neurons. These cultured cells form abundant synapses in

Microorganism and filamentous fungi drive evolution of plant synapses.

PubMed

Baluška, František; Mancuso, Stefano

2013-01-01

In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell-cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes.

Molecular organization of excitatory chemical synapses in the mammalian brain

NASA Astrophysics Data System (ADS)

Gundelfinger, E. D.; tom Dieck, S.

Chemical synapses are highly specialized cell-cell junctions designed for efficient signaling between nerve cells. Distinct cytoskeletal matrices are assembled at either side of the synaptic junction. The presynaptic cytomatrix at the active zone (CAZ) defines and organizes the site of neurotransmitter release from presynaptic nerve terminals. The postsynaptic density (PSD) tethers neurotransmitter receptors and the postsynaptic signal transduction machinery. Recent progress in the identification and characterization of novel CAZ and PSD components has revealed new insights into the molecular organization and assembly mechanisms of the synaptic neurotransmission apparatus. On the presynaptic side, Bassoon and Piccolo, two related giant proteins, are crucially involved in scaffolding the CAZ. On the postsynaptic side, two families of multi-domain adaptor proteins, the MAGuKs (membrane-associated guanylate kinase homologs) and the ProSAP (proline-rich synapse-associated protein, also termed Shank) family members are thought to be major organizing molecules of the PSD.

Changes in the expression of Th17 cell-associated cytokines in the development of rheumatic heart disease.

PubMed

Wen, Yun; Zeng, Zhiyu; Gui, Chun; Li, Lang; Li, Wenting

2015-01-01

Autoimmunity plays a critical role in the development of rheumatic heart disease (RHD). Recent studies have linked Th17 cells to the autoimmune mechanism associated with RHD. This study aimed to investigate changes in Th17 cell-related cytokine expression in acute and chronic RHD. We established a Lewis rat model of experimental RHD, which was induced by inactivated Group A streptococci and complete Freund's adjuvant. After 7- and 24-week intervention treatments, we measured serum levels of interleukin-17 (IL-17) and IL-6, key cytokines associated with Th17 cells, using a Luminex liquichip method, and levels of IL-17 and IL-6 in heart tissues using immunohistochemical assays. Moreover, expression levels of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues of human RHD patients were also measured using immunohistochemistry. Compared with the normal control group, serum IL-17 and IL-6 concentrations were significantly increased, and the expression levels of IL-17 and IL-6 in the mitral valve were also significantly increased in 7- or 24-week RHD rats (P<.017). Compared with the control group, expression of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues was significantly increased in RHD patients (P<.05). Our study suggested that the increased expression of Th17 cell-associated cytokines might play an important role in the pathogenesis and development of RHD. Copyright © 2015 Elsevier Inc. All rights reserved.

Invaginating Structures in Mammalian Synapses

PubMed Central

Petralia, Ronald S.; Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

2018-01-01

Invaginating structures at chemical synapses in the mammalian nervous system exist in presynaptic axon terminals, postsynaptic spines or dendrites, and glial processes. These invaginating structures can be divided into three categories. The first category includes slender protrusions invaginating into axonal terminals, postsynaptic spines, or glial processes. Best known examples of this category are spinules extending from postsynaptic spines into presynaptic terminals in forebrain synapses. Another example of this category are protrusions from inhibitory presynaptic terminals invaginating into postsynaptic neuronal somas. Regardless of the direction and location, the invaginating structures of the first category do not have synaptic active zones within the invagination. The second category includes postsynaptic spines invaginating into presynaptic terminals, whereas the third category includes presynaptic terminals invaginating into postsynaptic spines or dendrites. Unlike the first category, the second and third categories have active zones within the invagination. An example of the second category are mossy terminal synapses of the hippocampal CA3 region, in which enlarged spine-like structures invaginate partly or entirely into mossy terminals. An example of the third category is the neuromuscular junction (NMJ) where substantial invaginations of the presynaptic terminals invaginate into the muscle fibers. In the retina, rod and cone synapses have invaginating processes from horizontal and bipolar cells. Because horizontal cells act both as post and presynaptic structures, their invaginating processes represent both the second and third category. These invaginating structures likely play broad yet specialized roles in modulating neuronal cell signaling. PMID:29674962

Synaptic Plasticity and Translation Initiation

ERIC Educational Resources Information Center

Klann, Eric; Antion, Marcia D.; Banko, Jessica L.; Hou, Lingfei

2004-01-01

It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is…

The Marr and Albus Theories of the Cerebellum: Two Eary Models of Associative Memory

NASA Technical Reports Server (NTRS)

Albus, James S.

1989-01-01

The Marr and Albus theories of the cerebellum are compared and contrasted. They are shown to be similar in their analysis of the function of the mossy fibers, granule cells, Golgi cells, and Purkinje cells. They both predict motor learning in the parallel fiber synapses on the Purkinje dendrites mediated by concurrent climbing fiber input. This prediction has been confirmed by experimental evidence. In contrast, Marr predicts these synapses would be facilitated by learning, while Albus predicts they would be weakened. Experimental evidence confirms synaptic weakening.

Epsilon-aminocaproic acid influence in postoperative [corrected] bleeding and hemotransfusion [corrected] in mitral valve surgery.

PubMed

Benfatti, Ricardo Ádala; Carli, Amanda Ferreira; Silva, Guilherme Viotto Rodrigues da; Dias, Amaury Edgardo Mont'serrat Ávila Souza; Goldiano, José Anderson; Pontes, José Carlos Dorsa Vieira

2010-01-01

The epsilon aminocaproic acid is an antifibrinolytic used in cardiovascular surgery to inhibit the fibrinolysis and to reduce the bleeding after CPB. [corrected] To analyze the influence of the using of epsilon aminocaproic acid in the bleeding and in red-cell transfusion requirement in the first twenty-four hours postoperative of mitral valve surgery. Prospective studying, forty-two patients, randomized and divided in two equal groups: group #1 control and group #2--epsilon aminocaproic acid. In Group II were infused five grams of EACA in the induction of anesthesia, after full heparinization, CPB perfusate after reversal of heparin and one hour after the surgery, totaling 25 grams. In group I, saline solution was infused only in those moments. Group #1 showed average bleeding volume of 633.57 ± 305,7 ml, and Group #2, an average of 308.81 ± 210.1 ml, with significant statistic difference (P = 0.0003). Average volume of red-cell transfusion requirement in Groups 1 and 2 was, respectively, 942.86 ± 345.79 ml and 214.29 ± 330.58 ml, with significant difference (P < 0.0001). The epsilon aminocaproic acid was able to reduce the bleeding volume and the red-cell transfusion requirement in the immediate postoperative of patients submitted to mitral valve surgery.

Wide-field Diffuse Amacrine Cells in the Monkey Retina Contain Immunoreactive Cocaine- and Amphetamine-Regulated Transcript (CART)

PubMed Central

Liu, Weiley S.; Davis, Elizabeth P.; Lee, Stephen J.; Tseng, Luke; Chuang, Alice Z.; Whitaker, Christopher M.; Massey, Stephen C.; Sherman, Michael B.; Marshak, David W.

2016-01-01

The goals of this study were to localize the neuropeptide Cocaine- and Amphetamine-Regulated Transcript (CART) in primate retinas and to describe the morphology, neurotransmitter content and synaptic connections of the neurons that contain it. Using in situ hybridization, light and electron microscopic immunolabeling, CART was localized to GABAergic amacrine cells in baboon retinas. The CART-positive cells had thin, varicose dendrites that gradually descended through the inner plexiform layer and ramified extensively in the innermost stratum. They resembled two types of wide-field diffuse amacrine cells that had been described previously in macaque retinas using the Golgi method and also A17, serotonin-accumulating and waterfall cells of other mammals. The CART-positive cells received synapses from rod bipolar cell axons and made synapses onto the axons in a reciprocal configuration. The CART-positive cells also received synapses from other amacrine cells. Some of these were located on their primary dendrites, and the presynaptic cells there included dopaminergic amacrine cells. Although some CART-positive somas were localized in the ganglion cell layer, they did not contain the ganglion cell marker RNA binding protein with multiple splicing (RBPMS). Based on these results and electrophysiological studies in other mammals, the CART-positive amacrine cells would be expected to play a major role in the primary rod pathway of primates, providing feedback inhibition to rod bipolar cells. PMID:27568514

Clinical, echocardiographic, and Doppler imaging characteristics of mitral valve stenosis in two dogs.

PubMed

Fox, P R; Miller, M W; Liu, S K

1992-11-15

Mitral stenosis was diagnosed noninvasively by echocardiography and Doppler imaging in 2 Bull Terriers. Two-dimensional echocardiography revealed severe atrial and moderate left ventricular dilatation; severely reduced mitral valve opening excursion; doming of the cranial mitral valve leaflet into the left ventricle during diastole; thickened, nodular cranial mitral valve leaflets; and reduced mitral valve orifice. M-mode echocardiographic findings additionally indicated greatly diminished mitral valve E to F slope and abnormal caudal mitral valve leaflet motion. Color flow Doppler imaging revealed bright bursts of color with aliasing originating from the stenotic mitral valve orifice, extending into the left atrium during systole, and into the left atrium during diastole. Spectral Doppler recordings revealed transvalvular mitral valve gradients and prolonged pressure half-times. Necropsy performed on 1 dog revealed extremely thickened, nodular, and stiff mitral valves with short, thickened, and fused chordae tendineae. The diagnosis of mitral valve stenosis was easily facilitated with diagnostic ultrasonography.

The Changeable Nervous System: Studies On Neuroplasticity In Cerebellar Cultures

PubMed Central

Seil, Fredrick J.

2014-01-01

Circuit reorganization after injury was studied in a cerebellar culture model. When cerebellar cultures derived from newborn mice were exposed at explantation to a preparation of cytosine arabinoside that destroyed granule cells and oligodendrocytes and compromised astrocytes, Purkinje cells surviving in greater than usual numbers were unensheathed by astrocytic processes and received twice the control number of inhibitory axosomatic synapses. Purkinje cell axon collaterals sprouted and many of their terminals formed heterotypical synapses with other Purkinje cell dendritic spines. The resulting circuit reorganization preserved inhibition in the cerebellar cortex. Following this reorganization, replacement of the missing granule cells and glia was followed by a restitution of the normal circuitry. Most of these developmental and reconstructive changes were not dependent on neuronal activity, the major exception being inhibitory synaptogenesis. The full complement of inhibitory synapses did not develop in the absence of neuronal activity, which could be mitigated by application of exogenous TrkB receptor ligands. Inhibitory synaptogenesis could also be promoted by activity-induced release of endogenous TrkB receptor ligands or by antibody activation of the TrkB receptor. PMID:24933693

Microglia in CNS development: Shaping the brain for the future.

PubMed

Mosser, Coralie-Anne; Baptista, Sofia; Arnoux, Isabelle; Audinat, Etienne

Microglial cells are the resident macrophages of the central nervous system (CNS) and are mainly known for their roles in neuropathologies. However, major recent developments have revealed that these immune cells actively interact with neurons in physiological conditions and can modulate the fate and functions of synapses. Originating from myeloid precursors born in the yolk sac, microglial cells invade the CNS during early embryonic development. As a consequence they can potentially influence neuronal proliferation, migration and differentiation as well as the formation and maturation of neuronal networks, thereby contributing to the entire shaping of the CNS. We review here recent evidence indicating that microglial cells are indeed involved in crucial steps of the CNS development, including neuronal survival and apoptosis, axonal growth, migration of neurons, pruning of supernumerary synapses and functional maturation of developing synapses. We also discuss current hypotheses proposing that diverting microglial cells of their physiological functions, by promoting the expression of an immune phenotype during development, may be central to neurodevelopmental disorders such as autism, schizophrenia and epilepsy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lrit1, a Retinal Transmembrane Protein, Regulates Selective Synapse Formation in Cone Photoreceptor Cells and Visual Acuity.

PubMed

Ueno, Akiko; Omori, Yoshihiro; Sugita, Yuko; Watanabe, Satoshi; Chaya, Taro; Kozuka, Takashi; Kon, Tetsuo; Yoshida, Satoyo; Matsushita, Kenji; Kuwahara, Ryusuke; Kajimura, Naoko; Okada, Yasushi; Furukawa, Takahisa

2018-03-27

In the vertebrate retina, cone photoreceptors play crucial roles in photopic vision by transmitting light-evoked signals to ON- and/or OFF-bipolar cells. However, the mechanisms underlying selective synapse formation in the cone photoreceptor pathway remain poorly understood. Here, we found that Lrit1, a leucine-rich transmembrane protein, localizes to the photoreceptor synaptic terminal and regulates the synaptic connection between cone photoreceptors and cone ON-bipolar cells. Lrit1-deficient retinas exhibit an aberrant morphology of cone photoreceptor pedicles, as well as an impairment of signal transmission from cone photoreceptors to cone ON-bipolar cells. Furthermore, we demonstrated that Lrit1 interacts with Frmpd2, a photoreceptor scaffold protein, and with mGluR6, an ON-bipolar cell-specific glutamate receptor. Additionally, Lrit1-null mice showed visual acuity impairments in their optokinetic responses. These results suggest that the Frmpd2-Lrit1-mGluR6 axis regulates selective synapse formation in cone photoreceptors and is essential for normal visual function. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Zincergic innervation from the anterior olfactory nucleus to the olfactory bulb displays plastic responses after mitral cell loss.

PubMed

Airado, Carmen; Gómez, Carmela; Recio, Javier S; Baltanás, Fernando C; Weruaga, Eduardo; Alonso, José R

2008-12-01

Zinc ions are selectively accumulated in certain neurons (zinc-enriched neurons). The mouse olfactory bulb is richly innervated by zinc-enriched terminals. Here, the plasticity of the zincergic system was studied in the olfactory bulb of the Purkinje Cell Degeneration mutant mouse, an animal with specific postnatal neurodegeneration of the main projection neurons of the olfactory bulb. The analysis focused particularly on the anterior olfactory nucleus since most centrifugal afferents coming to the olfactory bulb arise from this structure. Zinc-enriched terminals in the olfactory bulb and zinc-enriched somata in the anterior olfactory nucleus were visualized after selenite injections. Immunohistochemistry against the vesicular zinc transporter was also carried out to confirm the distribution pattern of zinc-enriched terminals in the olfactory bulb. The mutant mice showed a clear reorganization of zincergic centrifugal projections from the anterior olfactory nucleus to the olfactory bulb. First, all zincergic contralateral neurons projecting to the olfactory bulb were absent in the mutant mice. Second, a significant increase in the number of stained somata was detected in the ipsilateral anterior olfactory nucleus. Since no noticeable changes were observed in the zinc-enriched terminals in the olfactory bulb, it is conceivable that mitral cell loss could induce a reorganization of zinc-enriched projections coming from the anterior olfactory nucleus, probably directed at balancing the global zincergic centrifugal modulation. These results show that zincergic anterior olfactory nucleus cells projecting to the olfactory bulb undergo plastic changes to adapt to the loss of mitral cells in the olfactory bulb of Purkinje Cell Degeneration mutant mice.

A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation.

PubMed

Godenschwege, Tanja A; Kristiansen, Lars V; Uthaman, Smitha B; Hortsch, Michael; Murphey, Rodney K

2006-01-10

Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation. We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin. We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.

Effects of Transforming Growth Factor Beta 1 in Cerebellar Development: Role in Synapse Formation

PubMed Central

Araujo, Ana P. B.; Diniz, Luan P.; Eller, Cristiane M.; de Matos, Beatriz G.; Martinez, Rodrigo; Gomes, Flávia C. A.

2016-01-01

Granule cells (GC) are the most numerous glutamatergic neurons in the cerebellar cortex and represent almost half of the neurons of the central nervous system. Despite recent advances, the mechanisms of how the glutamatergic synapses are formed in the cerebellum remain unclear. Among the TGF-β family, TGF-beta 1 (TGF-β1) has been described as a synaptogenic molecule in invertebrates and in the vertebrate peripheral nervous system. A recent paper from our group demonstrated that TGF-β1 increases the excitatory synapse formation in cortical neurons. Here, we investigated the role of TGF-β1 in glutamatergic cerebellar neurons. We showed that the expression profile of TGF-β1 and its receptor, TβRII, in the cerebellum is consistent with a role in synapse formation in vitro and in vivo. It is low in the early postnatal days (P1–P9), increases after postnatal day 12 (P12), and remains high until adulthood (P30). We also found that granule neurons express the TGF-β receptor mRNA and protein, suggesting that they may be responsive to the synaptogenic effect of TGF-β1. Treatment of granular cell cultures with TGF-β1 increased the number of glutamatergic excitatory synapses by 100%, as shown by immunocytochemistry assays for presynaptic (synaptophysin) and post-synaptic (PSD-95) proteins. This effect was dependent on TβRI activation because addition of a pharmacological inhibitor of TGF-β, SB-431542, impaired the formation of synapses between granular neurons. Together, these findings suggest that TGF-β1 has a specific key function in the cerebellum through regulation of excitatory synapse formation between granule neurons. PMID:27199658

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

PubMed

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

Structure, Distribution, and Function of Neuronal/Synaptic Spinules and Related Invaginating Projections

PubMed Central

Petralia, Ronald S.; Wang, Ya-Xian; Mattson, Mark P.; Yao, Pamela J.

2015-01-01

Neurons and especially their synapses often project long thin processes that can invaginate neighboring neuronal or glial cells. These “invaginating projections” can occur in almost any combination of postsynaptic, presynaptic, and glial processes. Invaginating projections provide a precise mechanism for one neuron to communicate or exchange material exclusively at a highly localized site on another neuron, e.g., to regulate synaptic plasticity. The best-known types are postsynaptic projections called “spinules” that invaginate into presynaptic terminals. Spinules seem to be most prevalent at large very active synapses. Here, we present a comprehensive review of all kinds of invaginating projections associated with both neurons in general and more specifically with synapses; we describe them in all animals including simple, basal metazoans. These structures may have evolved into more elaborate structures in some higher animal groups exhibiting greater synaptic plasticity. In addition to classic spinules and filopodial invaginations, we describe a variety of lesser-known structures such as amphid microvilli, spinules in giant mossy terminals and en marron/brush synapses, the highly specialized fish retinal spinules, the trophospongium, capitate projections, and fly gnarls, as well as examples in which the entire presynaptic or postsynaptic process is invaginated. These various invaginating projections have evolved to modify the function of a particular synapse, or to channel an effect to one specific synapse or neuron, without affecting those nearby. We discuss how they function in membrane recycling, nourishment, and cell signaling and explore how they might change in aging and disease. PMID:26007200

The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

PubMed Central

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M.; Malik, Mazhar; Brown, W. Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs. PMID:22615862

Advances in synapse formation: forging connections in the worm.

PubMed

Cherra, Salvatore J; Jin, Yishi

2015-01-01

Synapse formation is the quintessential process by which neurons form specific connections with their targets to enable the development of functional circuits. Over the past few decades, intense research efforts have identified thousands of proteins that localize to the pre- and postsynaptic compartments. Genetic dissection has provided important insights into the nexus of the molecular and cellular network, and has greatly advanced our knowledge about how synapses form and function physiologically. Moreover, recent studies have highlighted the complex regulation of synapse formation with the identification of novel mechanisms involving cell interactions from non-neuronal sources. In this review, we cover the conserved pathways required for synaptogenesis and place specific focus on new themes of synapse modulation arising from studies in Caenorhabditis elegans. For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article. © 2014 Wiley Periodicals, Inc.

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

PubMed

Mapelli, Lisa; Pagani, Martina; Garrido, Jesus A; D'Angelo, Egidio

2015-01-01

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses. Cerebellar LTP and LTD occur in all three main cerebellar subcircuits (granular layer, molecular layer, deep cerebellar nuclei) and correspondingly regulate the function of their three main neurons: granule cells (GrCs), Purkinje cells (PCs) and deep cerebellar nuclear (DCN) cells. All these neurons, in addition to be excited, are reached by feed-forward and feed-back inhibitory connections, in which LTP and LTD may either operate synergistically or homeostatically in order to control information flow through the circuit. Although the investigation of individual synaptic plasticities in vitro is essential to prove their existence and mechanisms, it is insufficient to generate a coherent view of their impact on network functioning in vivo. Recent computational models and cell-specific genetic mutations in mice are shedding light on how plasticity at multiple excitatory and inhibitory synapses might regulate neuronal activities in the cerebellar circuit and contribute to learning and memory and behavioral control.

[Aortic stenosis and mitral regurgitation complicated by hemolytic anemia and positive Direct Coombs test: a case report].

PubMed

Tamura, Shinjiro; Kitaoka, Hiroaki; Yamasaki, Naohito; Okawa, Makoto; Kubo, Toru; Matsumura, Yoshihisa; Furuno, Takashi; Takata, Jun; Nishinaga, Masanori; Sasaguri, Shiro; Doi, Yoshinori

2005-09-01

A 83-year-old man was admitted because of heart failure due to severe aortic stenosis and mitral regurgitation secondary to chordal rupture of the anterior leaflet. Mild anemia and elevated serum lactate dehydrogenase were present with reticulocytosis and haptoglobinemia. Direct Coombs test was positive. Coexistence of autoimmune hemolytic anemia was identified, but the main cause of his hemolysis was thought to be mechanical hemolysis due to stenotic valve and/or ruptured chordae because of the presence of red cell fragmentation. The patient successfully underwent double valve replacement. Improvement of anemia was coupled with reduction of the serum lactate dehydrogenase level. Valvular shear stress on the red cells and reduction of red cell deformability secondary to autoimmune hemolytic anemia were thought to be responsible for his hemolysis.

Dendrites of cerebellar granule cells correctly recognize their target axons for synaptogenesis in vitro.

PubMed

Ito, Shoko; Takeichi, Masatoshi

2009-08-04

Neural circuits are generated by precisely ordered synaptic connections among neurons, and this process is thought to rely on the ability of neurons to recognize specific partners. However, it is also known that neurons promiscuously form synapses with nonspecific partners, in particular when cultured in vitro, causing controversies about neural recognition mechanisms. Here we reexamined whether neurons can or cannot select particular partners in vitro. In the cerebellum, granule cell (GC) dendrites form synaptic connections specifically with mossy fibers, but not with climbing fibers. We cocultured GC neurons with pontine or inferior olivary axons, the major sources for mossy and climbing fibers, respectively, as well as with hippocampal axons as a control. The GC neurons formed synapses with pontine axons predominantly at the distal ends of their dendrites, reproducing the characteristic morphology of their synapses observed in vivo, whereas they failed to do so when combined with other axons. In the latter case, synaptic proteins could accumulate between axons and dendrites, but these synapses were randomly distributed throughout the contact sites, and also their synaptic vesicle recycling was anomalous. These observations suggest that GC dendrites can select their authentic partners for synaptogenesis even in vitro, forming the synapses with a GC-specific nature only with them.

Astrocyte lipid metabolism is critical for synapse development and function in vivo.

PubMed

van Deijk, Anne-Lieke F; Camargo, Nutabi; Timmerman, Jaap; Heistek, Tim; Brouwers, Jos F; Mogavero, Floriana; Mansvelder, Huibert D; Smit, August B; Verheijen, Mark H G

2017-04-01

The brain is considered to be autonomous in lipid synthesis with astrocytes producing lipids far more efficiently than neurons. Accordingly, it is generally assumed that astrocyte-derived lipids are taken up by neurons to support synapse formation and function. Initial confirmation of this assumption has been obtained in cell cultures, but whether astrocyte-derived lipids support synapses in vivo is not known. Here, we address this issue and determined the role of astrocyte lipid metabolism in hippocampal synapse formation and function in vivo. Hippocampal protein expression for the sterol regulatory element-binding protein (SREBP) and its target gene fatty acid synthase (Fasn) was found in astrocytes but not in neurons. Diminishing SREBP activity in astrocytes using mice in which the SREBP cleavage-activating protein (SCAP) was deleted from GFAP-expressing cells resulted in decreased cholesterol and phospholipid secretion by astrocytes. Interestingly, SCAP mutant mice showed more immature synapses, lower presynaptic protein SNAP-25 levels as well as reduced numbers of synaptic vesicles, indicating impaired development of the presynaptic terminal. Accordingly, hippocampal short-term and long-term synaptic plasticity were defective in mutant mice. These findings establish a critical role for astrocyte lipid metabolism in presynaptic terminal development and function in vivo. GLIA 2017;65:670-682. © 2017 Wiley Periodicals, Inc.

SMAD4 Defect Causes Auditory Neuropathy Via Specialized Disruption of Cochlear Ribbon Synapses in Mice.

PubMed

Liu, Ke; Ji, Fei; Yang, Guan; Hou, Zhaohui; Sun, Jianhe; Wang, Xiaoyu; Guo, Weiwei; Sun, Wei; Yang, Weiyan; Yang, Xiao; Yang, Shiming

2016-10-01

More than 100 genes have been associated with deafness. However, SMAD4 is rarely considered a contributor to deafness in humans, except for its well-defined role in cell differentiation and regeneration. Here, we report that a SMAD4 defect in mice can cause auditory neuropathy, which was defined as a mysterious hearing and speech perception disorder in human for which the genetic background remains unclear. Our study showed that a SMAD4 defect induces failed formation of cochlear ribbon synapse during the earlier stage of auditory development in mice. Further investigation found that there are nearly normal morphology of outer hair cells (OHCs) and post-synapse spiral ganglion nerves (SGNs) in SMAD4 conditional knockout mice (cKO); however, a preserved distortion product of otoacoustic emission (DPOAE) and cochlear microphonic (CM) still can be evoked in cKO mice. Moreover, a partial restoration of hearing detected by electric auditory brainstem response (eABR) has been obtained in the cKO mice using electrode stimuli toward auditory nerves. Additionally, the ribbon synapses in retina are not affected by this SMAD4 defect. Thus, our findings suggest that this SMAD4 defect causes auditory neuropathy via specialized disruption of cochlear ribbon synapses.

Blocking p75 (NTR) receptors alters polyinnervationz of neuromuscular synapses during development.

PubMed

Garcia, Neus; Tomàs, Marta; Santafe, Manel M; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

2011-09-01

High-resolution immunohistochemistry shows that the receptor protein p75(NTR) is present in the nerve terminal, muscle cell, and glial Schwann cell at the neuromuscular junction (NMJ) of postnatal rats (P4-P6) during the synapse elimination period. Blocking the receptor with the antibody anti-p75-192-IgG (1-5 μg/ml, 1 hr) results in reduced endplate potentials (EPPs) in mono- and polyinnervated synapses ex vivo, but the mean number of functional inputs per NMJ does not change for as long as 3 hr. Incubation with exogenous brain-derived neurotrophic factor (BDNF) for 1 hr (50 nM) resulted in a significant increase in the size of the EPPs in all nerve terminals, and preincubation with anti-p75-192-IgG prevented this potentiation. Long exposure (24 hr) in vivo of the NMJs to the antibody anti-p75-192-IgG (1-2 μg/ml) results in a delay of postnatal synapse elimination and even some regrowth of previously withdrawn axons, but also in some acceleration of the morphologic maturation of the postsynaptic nicotinic acetylcholine receptor (nAChR) clusters. The results indicate that p75(NTR) is involved in both ACh release and axonal retraction during postnatal axonal competition and synapse elimination. Copyright © 2011 Wiley-Liss, Inc.

Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons

PubMed Central

Neuman, Krystina M.; Molina-Campos, Elizabeth; Musial, Timothy F.; Price, Andrea L.; Oh, Kwang-Jin; Wolke, Malerie L.; Buss, Eric W.; Scheff, Stephen W.; Mufson, Elliott J.; Nicholson, Daniel A.

2014-01-01

Alzheimer’s disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity. PMID:25031178

Effects of Neuromodulation on Excitatory-Inhibitory Neural Network Dynamics Depend on Network Connectivity Structure

NASA Astrophysics Data System (ADS)

Rich, Scott; Zochowski, Michal; Booth, Victoria

2018-01-01

Acetylcholine (ACh), one of the brain's most potent neuromodulators, can affect intrinsic neuron properties through blockade of an M-type potassium current. The effect of ACh on excitatory and inhibitory cells with this potassium channel modulates their membrane excitability, which in turn affects their tendency to synchronize in networks. Here, we study the resulting changes in dynamics in networks with inter-connected excitatory and inhibitory populations (E-I networks), which are ubiquitous in the brain. Utilizing biophysical models of E-I networks, we analyze how the network connectivity structure in terms of synaptic connectivity alters the influence of ACh on the generation of synchronous excitatory bursting. We investigate networks containing all combinations of excitatory and inhibitory cells with high (Type I properties) or low (Type II properties) modulatory tone. To vary network connectivity structure, we focus on the effects of the strengths of inter-connections between excitatory and inhibitory cells (E-I synapses and I-E synapses), and the strengths of intra-connections among excitatory cells (E-E synapses) and among inhibitory cells (I-I synapses). We show that the presence of ACh may or may not affect the generation of network synchrony depending on the network connectivity. Specifically, strong network inter-connectivity induces synchronous excitatory bursting regardless of the cellular propensity for synchronization, which aligns with predictions of the PING model. However, when a network's intra-connectivity dominates its inter-connectivity, the propensity for synchrony of either inhibitory or excitatory cells can determine the generation of network-wide bursting.

Active Sampling State Dynamically Enhances Olfactory Bulb Odor Representation.

PubMed

Jordan, Rebecca; Fukunaga, Izumi; Kollo, Mihaly; Schaefer, Andreas T

2018-06-27

The olfactory bulb (OB) is the first site of synaptic odor information processing, yet a wealth of contextual and learned information has been described in its activity. To investigate the mechanistic basis of contextual modulation, we use whole-cell recordings to measure odor responses across rapid learning episodes in identified mitral/tufted cells (MTCs). Across these learning episodes, diverse response changes occur already during the first sniff cycle. Motivated mice develop active sniffing strategies across learning that robustly correspond to the odor response changes, resulting in enhanced odor representation. Evoking fast sniffing in different behavioral states demonstrates that response changes during active sampling exceed those predicted from feedforward input alone. Finally, response changes are highly correlated in tufted cells, but not mitral cells, indicating there are cell-type-specific effects on odor representation during active sampling. Altogether, we show that active sampling is strongly associated with enhanced OB responsiveness on rapid timescales. Copyright © 2018 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Development and Maturation of the Neuromuscular Junciton in Cell Culture Under Conditions of Simulated Zero-gravity

NASA Technical Reports Server (NTRS)

Gruener, R.

1985-01-01

Alterations in gravitational conditions which alter the normal development and interactions of nerve and muscle cells grown in culture is examined. Clinostat conditions, similating Og, which produce changes in cell morphology and growth patterns is studied. Data show that rotation of cocultures of nerve and muscle cells results in morphologic changes which are predicted to significantly alter the functional interactions between the elements of a prototypic synapse. It is further predicted that similar alterations may occur in central synapses which may therefore affect the development of the central nervous system when subjected to altered gravitational conditions.

Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time

PubMed Central

Rudd-Schmidt, Jesse A.; Lopez, Jamie A.; Ramsbottom, Kelly M.; Mannering, Stuart I.; Andrews, Daniel M.; Voskoboinik, Ilia

2015-01-01

Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf-deficient infants suffer a fatal “cytokine storm” resulting from macrophage overactivation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTLs/NK cells and that interferon-γ (IFN-γ) directly invokes the activation and secondary overproduction of proinflammatory IL-6 from naive macrophages. Furthermore, using live cell microscopy to visualize hundreds of synapses formed between wild-type, Prf-null, or GzmA/B-null CTLs/NK cells and their targets in real time, we show that hypersecretion of IL-2, TNF, IFN-γ, and various chemokines is linked to failed disengagement of Prf- or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from ∼8 to >40 min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase dependent, as delaying target cell death with various forms of caspase blockade also prevented their disengagement from fully competent CTLs/NK cells and caused cytokine hypersecretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells. PMID:25732304

AII amacrine cells discriminate between heterocellular and homocellular locations when assembling connexin36-containing gap junctions

PubMed Central

Meyer, Arndt; Hilgen, Gerrit; Dorgau, Birthe; Sammler, Esther M.; Weiler, Reto; Monyer, Hannah; Dedek, Karin; Hormuzdi, Sheriar G.

2014-01-01

ABSTRACT Electrical synapses (gap junctions) rapidly transmit signals between neurons and are composed of connexins. In neurons, connexin36 (Cx36) is the most abundant isoform; however, the mechanisms underlying formation of Cx36-containing electrical synapses are unknown. We focus on homocellular and heterocellular gap junctions formed by an AII amacrine cell, a key interneuron found in all mammalian retinas. In mice lacking native Cx36 but expressing a variant tagged with enhanced green fluorescent protein at the C-terminus (KO-Cx36-EGFP), heterocellular gap junctions formed between AII cells and ON cone bipolar cells are fully functional, whereas homocellular gap junctions between two AII cells are not formed. A tracer injected into an AII amacrine cell spreads into ON cone bipolar cells but is excluded from other AII cells. Reconstruction of Cx36–EGFP clusters on an AII cell in the KO-Cx36-EGFP genotype confirmed that the number, but not average size, of the clusters is reduced – as expected for AII cells lacking a subset of electrical synapses. Our studies indicate that some neurons exhibit at least two discriminatory mechanisms for assembling Cx36. We suggest that employing different gap-junction-forming mechanisms could provide the means for a cell to regulate its gap junctions in a target-cell-specific manner, even if these junctions contain the same connexin. PMID:24463820

Emerging Synaptic Molecules as Candidates in the Etiology of Neurological Disorders

PubMed Central

Torres, Viviana I.; Vallejo, Daniela

2017-01-01

Synapses are complex structures that allow communication between neurons in the central nervous system. Studies conducted in vertebrate and invertebrate models have contributed to the knowledge of the function of synaptic proteins. The functional synapse requires numerous protein complexes with specialized functions that are regulated in space and time to allow synaptic plasticity. However, their interplay during neuronal development, learning, and memory is poorly understood. Accumulating evidence links synapse proteins to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. In this review, we describe the way in which several proteins that participate in cell adhesion, scaffolding, exocytosis, and neurotransmitter reception from presynaptic and postsynaptic compartments, mainly from excitatory synapses, have been associated with several synaptopathies, and we relate their functions to the disease phenotype. PMID:28331639

Voltage-Dependent Intrinsic Bursting in Olfactory Bulb Golgi Cells

ERIC Educational Resources Information Center

Pressler, R. Todd; Rozman, Peter A.; Strowbridge, Ben W.

2013-01-01

In the mammalian olfactory bulb (OB), local synaptic circuits modulate the evolving pattern of activity in mitral and tufted cells following olfactory sensory stimulation. GABAergic granule cells, the most numerous interneuron subtype in this brain region, have been extensively studied. However, classic studies using Golgi staining methods…

Determination of correlation between backflow volume and mitral valve leaflet young modulus from two dimensional echocardiogram images

NASA Astrophysics Data System (ADS)

Jong, Rudiyanto P.; Osman, Kahar; Adib, M. Azrul Hisham M.

2012-06-01

Mitral valve prolapse without proper monitoring might lead to a severe mitral valve failure which eventually leads to a sudden death. Additional information on the mitral valve leaflet condition against the backflow volume would be an added advantage to the medical practitioner for their decision on the patients' treatment. A study on two dimensional echocardiography images has been conducted and the correlations between the backflow volume of the mitral regurgitation and mitral valve leaflet Young modulus have been obtained. Echocardiogram images were analyzed on the aspect of backflow volume percentage and mitral valve leaflet dimensions on different rates of backflow volume. Young modulus values for the mitral valve leaflet were obtained by using the principle of elastic deflection and deformation on the mitral valve leaflet. The results show that the backflow volume increased with the decrease of the mitral valve leaflet Young modulus which also indicate the condition of the mitral valve leaflet approaching failure at high backflow volumes. Mitral valve leaflet Young modulus values obtained in this study agreed with the healthy mitral valve leaflet Young modulus from the literature. This is an initial overview of the trend on the prediction of the behaviour between the fluid and the structure of the blood and the mitral valve which is extendable to a larger system of prediction on the mitral valve leaflet condition based on the available echocardiogram images.

Aortic or Mitral Valve Replacement With the Biocor and Biocor Supra

ClinicalTrials.gov

2017-04-26

Aortic Valve Insufficiency; Aortic Valve Regurgitation; Aortic Valve Stenosis; Aortic Valve Incompetence; Mitral Valve Insufficiency; Mitral Valve Regurgitation; Mitral Valve Stenosis; Mitral Valve Incompetence

Pathophysiology of Degenerative Mitral Regurgitation: New 3-Dimensional Imaging Insights.

PubMed

Antoine, Clemence; Mantovani, Francesca; Benfari, Giovanni; Mankad, Sunil V; Maalouf, Joseph F; Michelena, Hector I; Enriquez-Sarano, Maurice

2018-01-01

Despite its high prevalence, little is known about mechanisms of mitral regurgitation in degenerative mitral valve disease apart from the leaflet prolapse itself. Mitral valve is a complex structure, including mitral annulus, mitral leaflets, papillary muscles, chords, and left ventricular walls. All these structures are involved in physiological and pathological functioning of this valvuloventricular complex but up to now were difficult to analyze because of inherent limitations of 2-dimensional imaging. The advent of 3-dimensional echocardiography, computed tomography, and cardiac magnetic resonance imaging overcoming these limitations provides new insights into mechanistic analysis of degenerative mitral regurgitation. This review will detail the contribution of quantitative and qualitative dynamic analysis of mitral annulus and mitral leaflets by new imaging methods in the understanding of degenerative mitral regurgitation pathophysiology. © 2018 American Heart Association, Inc.

Specialized postsynaptic morphology enhances neurotransmitter dilution and high-frequency signaling at an auditory synapse.

PubMed

Graydon, Cole W; Cho, Soyoun; Diamond, Jeffrey S; Kachar, Bechara; von Gersdorff, Henrique; Grimes, William N

2014-06-11

Sensory processing in the auditory system requires that synapses, neurons, and circuits encode information with particularly high temporal and spectral precision. In the amphibian papillia, sound frequencies up to 1 kHz are encoded along a tonotopic array of hair cells and transmitted to afferent fibers via fast, repetitive synaptic transmission, thereby promoting phase locking between the presynaptic and postsynaptic cells. Here, we have combined serial section electron microscopy, paired electrophysiological recordings, and Monte Carlo diffusion simulations to examine novel mechanisms that facilitate fast synaptic transmission in the inner ear of frogs (Rana catesbeiana and Rana pipiens). Three-dimensional anatomical reconstructions reveal specialized spine-like contacts between individual afferent fibers and hair cells that are surrounded by large, open regions of extracellular space. Morphologically realistic diffusion simulations suggest that these local enlargements in extracellular space speed transmitter clearance and reduce spillover between neighboring synapses, thereby minimizing postsynaptic receptor desensitization and improving sensitivity during prolonged signal transmission. Additionally, evoked EPSCs in afferent fibers are unaffected by glutamate transporter blockade, suggesting that transmitter diffusion and dilution, and not uptake, play a primary role in speeding neurotransmission and ensuring fidelity at these synapses. Copyright © 2014 the authors 0270-6474/14/348358-15$15.00/0.

Building tolerance by dismantling synapses: inhibitory receptor signaling in natural killer cells.

PubMed

Huse, Morgan; Catherine Milanoski, S; Abeyweera, Thushara P

2013-01-01

Cell surface receptors bearing immunotyrosine-based inhibitory motifs (ITIMs) maintain natural killer (NK) cell tolerance to normal host tissues. These receptors are difficult to analyze mechanistically because they block activating responses in a rapid and comprehensive manner. The advent of high-resolution single cell imaging techniques has enabled investigators to explore the cell biological basis of the inhibitory response. Recent studies using these approaches indicate that ITIM-containing receptors function at least in part by structurally undermining the immunological synapse between the NK cell and its target. In this review, we discuss these new advances and how they might relate to what is known about the biochemistry of inhibitory signaling in NK cells and other cell types. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

Synapse Specificity of Long-Term Potentiation Breaks Down with Aging

ERIC Educational Resources Information Center

Ris, Laurence; Godaux, Emile

2007-01-01

Memory shows age-related decline. According to the current prevailing theoretical model, encoding of memories relies on modifications in the strength of the synapses connecting the different cells within a neuronal network. The selective increases in synaptic weight are thought to be biologically implemented by long-term potentiation (LTP). Here,…

Bidirectional synaptic plasticity in the cerebellum-like mammalian dorsal cochlear nucleus

NASA Astrophysics Data System (ADS)

Fujino, Kiyohiro; Oertel, Donata

2003-01-01

The dorsal cochlear nucleus integrates acoustic with multimodal sensory inputs from widespread areas of the brain. Multimodal inputs are brought to spiny dendrites of fusiform and cartwheel cells in the molecular layer by parallel fibers through synapses that are subject to long-term potentiation and long-term depression. Acoustic cues are brought to smooth dendrites of fusiform cells in the deep layer by auditory nerve fibers through synapses that do not show plasticity. Plasticity requires Ca2+-induced Ca2+ release; its sensitivity to antagonists of N-methyl-D-aspartate and metabotropic glutamate receptors differs in fusiform and cartwheel cells.

Rare Combination of Pathologies Causing Mitral Stenosis and Mitral Regurgitation: A Case Report.

PubMed

Nair, Anupama K; Chowdhuri, Kuntal Roy; Radhakrishnan, Sitaraman; Iyer, Krishna S; Saxena, Manish

2018-01-01

A supramitral ring is a rare cause of mitral stenosis, while an isolated mitral valve cleft is a rare cause of congenital mitral regurgitation. Fortunately, both the lesions are known to have good outcomes after surgical correction. Although each is known to be associated with a variety of other structural heart defects, their coexistence has not been reported previously. We report a case of a three- and half-year-old boy detected to have a rare combination of supramitral ring producing severe mitral stenosis with a coexisting cleft in the anterior leaflet of mitral valve causing severe mitral regurgitation. The patient underwent successful surgical repair with resolution of both mitral stenosis and regurgitation.

Inoue Balloon Mitral Valvotomy in a 4-Year-Old Boy

PubMed Central

Kapoor, Aditya; Moorthy, Nagaraja; Kumar, Sudeep

2012-01-01

Mitral stenosis in children often has a fulminant and rapid course. Percutaneous transvenous mitral commissurotomy is accepted as the treatment of choice for mitral stenosis not only in adults, but also in younger patients who have pliable valves. Balloon mitral valvotomy has yielded good immediate and long-term results. Herein, we report successful Inoue balloon mitral valvotomy in a 4-year-old boy who had severe, symptomatic rheumatic mitral stenosis. To our knowledge, our patient is the youngest to have undergone this procedure. In addition to the case description, we discuss the features of juvenile rheumatic mitral stenosis and several technical aspects of performing the Inoue balloon mitral valvotomy procedure in children. PMID:22412242

Unravelling how βCaMKII controls the direction of plasticity at parallel fibre-Purkinje cell synapses

NASA Astrophysics Data System (ADS)

Pinto, Thiago M.; Schilstra, Maria J.; Steuber, Volker; Roque, Antonio C.

2015-12-01

Long-term plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses is thought to mediate cerebellar motor learning. It is known that calcium-calmodulin dependent protein kinase II (CaMKII) is essential for plasticity in the cerebellum. Recently, Van Woerden et al. demonstrated that the β isoform of CaMKII regulates the bidirectional inversion of PF-PC plasticity. Because the cellular events that underlie these experimental findings are still poorly understood, our work aims at unravelling how β CaMKII controls the direction of plasticity at PF-PC synapses. We developed a bidirectional plasticity model that replicates the experimental observations by Van Woerden et al. Simulation results obtained from this model indicate the mechanisms that underlie the bidirectional inversion of cerebellar plasticity. As suggested by Van Woerden et al., the filamentous actin binding enables β CaMKII to regulate the bidirectional plasticity at PF-PC synapses. Our model suggests that the reversal of long-term plasticity in PCs is based on a combination of mechanisms that occur at different calcium concentrations.

The CNS connectome of a tadpole larva of Ciona intestinalis (L.) highlights sidedness in the brain of a chordate sibling

PubMed Central

Ryan, Kerrianne; Lu, Zhiyuan; Meinertzhagen, Ian A

2016-01-01

Left-right asymmetries in brains are usually minor or cryptic. We report brain asymmetries in the tiny, dorsal tubular nervous system of the ascidian tadpole larva, Ciona intestinalis. Chordate in body plan and development, the larva provides an outstanding example of brain asymmetry. Although early neural development is well studied, detailed cellular organization of the swimming larva’s CNS remains unreported. Using serial-section EM we document the synaptic connectome of the larva’s 177 CNS neurons. These formed 6618 synapses including 1772 neuromuscular junctions, augmented by 1206 gap junctions. Neurons are unipolar with at most a single dendrite, and few synapses. Some synapses are unpolarised, others form reciprocal or serial motifs; 922 were polyadic. Axo-axonal synapses predominate. Most neurons have ciliary organelles, and many features lack structural specialization. Despite equal cell numbers on both sides, neuron identities and pathways differ left/right. Brain vesicle asymmetries include a right ocellus and left coronet cells. DOI: http://dx.doi.org/10.7554/eLife.16962.001 PMID:27921996

Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction.

PubMed

Tomàs, Josep M; Garcia, Neus; Lanuza, Maria A; Nadal, Laura; Tomàs, Marta; Hurtado, Erica; Simó, Anna; Cilleros, Víctor

2017-01-01

Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh) receptors (subtypes mAChR; M 1 , M 2 and M 4 ), adenosine receptors (AR; A 1 and A 2A ) and the tropomyosin-related kinase B receptor (TrkB), among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC), to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A 1 , M 1 and TrkB operate mainly by stimulating PKC whereas A 2A , M 2 and M 4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC) in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ). This hypothesis is supported by: (i) the tonic effect (shown by using selective inhibitors) of several membrane receptors that accelerates axon loss between postnatal days P5-P9; (ii) the synergistic, antagonic and modulatory effects (shown by paired inhibition) of the receptors on axonal loss; (iii) the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various combinations of selective and specific PKA and PKC inhibitors could help to elucidate the role of these kinases in synapse maturation.

Respiration Gates Sensory Input Responses in the Mitral Cell Layer of the Olfactory Bulb

PubMed Central

Short, Shaina M.; Morse, Thomas M.; McTavish, Thomas S.; Shepherd, Gordon M.; Verhagen, Justus V.

2016-01-01

Respiration plays an essential role in odor processing. Even in the absence of odors, oscillating excitatory and inhibitory activity in the olfactory bulb synchronizes with respiration, commonly resulting in a burst of action potentials in mammalian mitral/tufted cells (MTCs) during the transition from inhalation to exhalation. This excitation is followed by inhibition that quiets MTC activity in both the glomerular and granule cell layers. Odor processing is hypothesized to be modulated by and may even rely on respiration-mediated activity, yet exactly how respiration influences sensory processing by MTCs is still not well understood. By using optogenetics to stimulate discrete sensory inputs in vivo, it was possible to temporally vary the stimulus to occur at unique phases of each respiration. Single unit recordings obtained from the mitral cell layer were used to map spatiotemporal patterns of glomerular evoked responses that were unique to stimulations occurring during periods of inhalation or exhalation. Sensory evoked activity in MTCs was gated to periods outside phasic respiratory mediated firing, causing net shifts in MTC activity across the cycle. In contrast, odor evoked inhibitory responses appear to be permitted throughout the respiratory cycle. Computational models were used to further explore mechanisms of inhibition that can be activated by respiratory activity and influence MTC responses. In silico results indicate that both periglomerular and granule cell inhibition can be activated by respiration to internally gate sensory responses in the olfactory bulb. Both the respiration rate and strength of lateral connectivity influenced inhibitory mechanisms that gate sensory evoked responses. PMID:28005923

Percutaneous transluminal mitral commissurotomy for rheumatic mitral stenosis in a 5-year-old child.

PubMed

Ullah, Maad; Sultan, Mehboob; Akbar, Hajira; Sadiq, Nadeem

2012-06-01

We report a 5-year-old boy weighing 11 kg, with severe mitral valve stenosis of rheumatic aetiology, who underwent successful percutaneous transluminal mitral commissurotomy (PTMC) with valvuloplasty balloon. Postprocedural mean pressure gradient across the mitral valve decreased to 6 mmHg from an initially recorded value of 22 mmHg. In addition to symptomatic improvement, the mitral valvular area increased from 0.4 to 0.8 cm(2) without significant change in mitral regurgitation. At 1- and 3-month follow up, transthoracic echocardiography revealed further improvement with an increase in mitral valve area to 1.0 cm(2), a decrease in pulmonary arterial pressure, and a mean mitral valve pressure gradient of 8 mmHg with trivial mitral regurgitation. To best of our knowledge, this is the first successful PTMC procedure performed in the youngest and smallest ever reported child with rheumatic mitral stenosis (MS). We conclude that PTMC with valvuloplasty balloon could be a logical alternative to surgery in young patients with rheumatic MS.

Effectiveness of Percutaneous Balloon Mitral Valvuloplasty for Rheumatic Mitral Stenosis with Mild to Severe Mitral Regurgitation

PubMed Central

Lu, LinXiang; Hong, Lang; Fang, Jun; Chen, LiangLong

2016-01-01

This study is designed to test whether percutaneous balloon mitral valvuloplasty (PBMV) is effective for rheumatic mitral stenosis in Chinese patients with moderate to severe mitral regurgitation. Fifty-six patients with rheumatic mitral valve stenosis were divided into the mild, moderate, and severe regurgitation groups. Cardiac ultrasonography was measured before and 1 to 2 days after PBMV. Following PBMV, the mitral orifice was enlarged, and the left atrial diameter was reduced in the 3 patient groups. The enlargement of the mitral orifice in the mild regurgitation group was greater than that observed in the moderate and severe regurgitation groups. The size of the regurgitation area increased in the mild regurgitation group and decreased in the moderate and severe regurgitation groups, with the decrease in the severe regurgitation group being greater than that in the moderate regurgitation group. Therefore, PBMV is effective for treating rheumatic mitral stenosis in Chinese patients with mild to severe mitral regurgitation. PMID:27034933

Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus

PubMed Central

Kitahara, Yosuke; Ohta, Keisuke; Hasuo, Hiroshi; Shuto, Takahide; Kuroiwa, Mahomi; Sotogaku, Naoki; Togo, Akinobu; Nakamura, Kei-ichiro; Nishi, Akinori

2016-01-01

A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission. PMID:26788851

Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids.

PubMed

Wang, Yanqing; Burrell, Brian D

2016-08-01

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl(-) gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl(-) export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl(-) equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl(-) import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl(-) import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl(-) gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions. Copyright © 2016 the American Physiological Society.

Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

PubMed Central

Wang, Yanqing

2016-01-01

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl− gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl− export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmech neurons, which are depolarized by GABA due to an elevated Cl− equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl− import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npoly neurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl− import. Consequently, the primary role of elevated ECl may be to protect Npoly synapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npoly synapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmech synapses. These findings demonstrate a critical role of differences in Cl− gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions. PMID:27226449

Cationic influences upon synaptic transmission at the hair cell-afferent fiber synapse of the frog

NASA Technical Reports Server (NTRS)

Cochran, S. L.

1995-01-01

The concentrations of inorganic cations (K+, Na+, and Ca2+) bathing the isolated frog labyrinth were varied in order to assess their role in influencing and mediating synaptic transmission at the hair cell-afferent fiber synapse. Experiments employed intracellular recordings of synaptic activity from VIIIth nerve afferents. Recordings were digitized continuously at 50 kHz, and excitatory postsynaptic potentials were detected and parameters quantified by computer algorithms. Particular attention was focused on cationic effects upon excitatory postsynaptic potential frequency of occurrence and excitatory postsynaptic potential amplitude, in order to discriminate between pre- and postsynaptic actions. Because the small size of afferents preclude long term stable recordings, alterations in cationic concentrations were applied transiently and their peak effects on synaptic activity were assessed. Increases in extracellular K+ concentration of a few millimolar produced a large increase in the frequency of occurrence of excitatory postsynaptic potentials with little change in amplitude, indicating that release of transmitter from the hair cell is tightly coupled to its membrane potential. Increasing extracellular Na+ concentration resulted in an increase in excitatory postsynaptic potential amplitude with no significant change in excitatory postsynaptic potential frequency of occurrence, suggesting that the transmitter-gated subsynaptic channel conducts Na+ ions. Decreases in extracellular Ca2+ concentration had little effect upon excitatory postsynaptic potential frequency, but increased excitatory postsynaptic potential frequency and amplitude. These findings suggest that at higher concentrations Ca2+ act presynaptically to prevent transmitter release and postsynaptically to prevent Na+ influx during the generation of the excitatory postsynaptic potential. The influences of these ions on synaptic activity at this synapse are remarkably similar to those reported at the vertebrate neuromuscular junction. The major differences between these two synapses are the neurotransmitters and the higher resting release rate and higher sensitivity of release to increased K+ concentrations of the hair cells over that of motor nerve terminals. These differences reflect the functional roles of the two synapses: the motor nerve terminal response in an all-or-nothing signal consequent from action potential invasion, while the hair cell releases transmitter in a graded fashion, proportionate to the extent of stereocilial deflection. Despite these differences between the two junctions, the similar actions of these elemental cations upon synaptic function at each implies that these ions may participate similarly in the operations of other synapses, independent of the neurotransmitter type.(ABSTRACT TRUNCATED AT 400 WORDS).

Normal and abnormal secretion by haemopoietic cells

PubMed Central

STINCHCOMBE, JANE C; GRIFFITHS, GILLIAN M

2001-01-01

The secretory lysosomes found in haemopoietic cells provide a very efficient mechanism for delivering the effector proteins of many immune cells in response to antigen recognition. Although secretion shows some similarities to the secretion of specialized granules in other secretory cell types, some aspects of secretory lysosome release appear to be unique to melanocytes and cells of the haemopoietic lineage. Mast cells and platelets have provided excellent models for studying secretion, but recent advances in characterizing the immunological synapse allow a very fine dissection of the secretory process in T lymphocytes. These studies show that secretory lysosomes are secreted from the centre of the talin ring at the synapse. Proper secretion requires a series of Rab and cytoskeletal elements which play critical roles in the specialized secretion of lysosomes in haemopoietic cells. PMID:11380687

Synaptogenesis in the CNS: An Odyssey from Wiring Together to Firing Together

PubMed Central

Munno, David W; Syed, Naweed I

2003-01-01

To acquire a better comprehension of nervous system function, it is imperative to understand how synapses are assembled during development and subsequently altered throughout life. Despite recent advances in the fields of neurodevelopment and synaptic plasticity, relatively little is known about the mechanisms that guide synapse formation in the central nervous system (CNS). Although many structural components of the synaptic machinery are pre-assembled prior to the arrival of growth cones at the site of their potential targets, innumerable changes, central to the proper wiring of the brain, must subsequently take place through contact-mediated cell-cell communications. Identification of such signalling molecules and a characterization of various events underlying synaptogenesis are pivotal to our understanding of how a brain cell completes its odyssey from ‘wiring together to firing together’. Here we attempt to provide a comprehensive overview that pertains directly to the cellular and molecular mechanisms of selection, formation and refinement of synapses during the development of the CNS in both vertebrates and invertebrates. PMID:12897180

Management of mitral regurgitation in Marfan syndrome: Outcomes of valve repair versus replacement and comparison with myxomatous mitral valve disease.

PubMed

Helder, Meghana R K; Schaff, Hartzell V; Dearani, Joseph A; Li, Zhuo; Stulak, John M; Suri, Rakesh M; Connolly, Heidi M

2014-09-01

The study objective was to evaluate patients with Marfan syndrome and mitral valve regurgitation undergoing valve repair or replacement and to compare them with patients undergoing repair for myxomatous mitral valve disease. We reviewed the medical records of consecutive patients with Marfan syndrome treated surgically between March 17, 1960, and September 12, 2011, for mitral regurgitation and performed a subanalysis of those with repairs compared with case-matched patients with myxomatous mitral valve disease who had repairs (March 14, 1995, to July 5, 2013). Of 61 consecutive patients, 40 underwent mitral repair and 21 underwent mitral replacement (mean [standard deviation] age, 40 [18] vs 31 [19] years; P = .09). Concomitant aortic surgery was performed to a similar extent (repair, 45% [18/40] vs replacement, 43% [9/21]; P = .87). Ten-year survival was significantly better in patients with Marfan syndrome with mitral repair than in those with replacement (80% vs 41%; P = .01). Mitral reintervention did not differ between mitral repair and replacement (cumulative risk of reoperation, 27% vs 15%; P = .64). In the matched cohort, 10-year survival after repair was similar for patients with Marfan syndrome and myxomatous mitral disease (84% vs 78%; P = .63), as was cumulative risk of reoperation (17% vs 12%; P = .61). Patients with Marfan syndrome and mitral regurgitation have better survival with repair than with replacement. Survival and risk of reoperation for patients with Marfan syndrome were similar to those for patients with myxomatous mitral disease. These results support the use of mitral valve repair in patients with Marfan syndrome and moderate or more mitral regurgitation, including those having composite replacement of the aortic root. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Transsynaptic Teneurin Signaling in Neuromuscular Synapse Organization and Target Choice

PubMed Central

Mosca, Timothy J.; Hong, Weizhe; Dani, Vardhan S.; Favaloro, Vincenzo; Luo, Liqun

2012-01-01

Synapse assembly requires transsynaptic signals between the pre- and postsynapse1, but the understanding of essential organizational molecules remains incomplete2. Teneurins are conserved, EGF-repeat containing transmembrane proteins with large extracellular domains3. Here we show that two Drosophila Teneurins, Ten-m and Ten-a, are required for neuromuscular synapse organization and target selection. Ten-a is presynaptic while Ten-m is mostly postsynaptic; neuronal Ten-a and muscle Ten-m form a complex in vivo. Pre- or postsynaptic Teneurin perturbations cause severe synapse loss and impair many facets of organization transsynaptically and cell-autonomously. These include defects in active zone apposition, release sites, membrane and vesicle organization, and synaptic transmission. Moreover, the presynaptic microtubule and postsynaptic spectrin cytoskeletons are severely disrupted, suggesting a mechanism whereby Teneurins organize the cytoskeleton, which in turn affects other aspects of synapse development. Supporting this, Ten-m physically interacts with α-spectrin. Genetic analyses of teneurin and neuroligin reveal their differential roles that synergize to promote synapse assembly. Finally, at elevated endogenous levels, Ten-m regulates specific motoneuron-muscle target selection. Our study identifies the Teneurins as a key bi-directional transsynaptic signal in general synapse organization, and demonstrates that such a molecule can also regulate target selection. PMID:22426000

Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian

PubMed Central

Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A.; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg–Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture. PMID:23610557

Transsynaptic coordination of synaptic growth, function, and stability by the L1-type CAM Neuroglian.

PubMed

Enneking, Eva-Maria; Kudumala, Sirisha R; Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg-Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture.

A potential reservoir of immature dopaminergic replacement neurons in the adult mammalian olfactory bulb.

PubMed

Pignatelli, Angela; Ackman, James B; Vigetti, Davide; Beltrami, Antonio P; Zucchini, Silvia; Belluzzi, Ottorino

2009-02-01

A significant fraction of the interneurons added in adulthood to the glomerular layer (GL) of the olfactory bulb (OB) are dopaminergic (DA). In the OB, DA neurons are restricted to the GL, but using transgenic mice expressing eGFP under the tyrosine hydroxylase (TH) promoter, we also detected the presence of TH-GFP+ cells in the mitral and external plexiform layers. We hypothesized that these could be adult-generated neurons committed to become DA but not yet entirely differentiated. Accordingly, TH-GFP+ cells outside the GL exhibit functional properties (appearance of pacemaker currents, synaptic connection with the olfactory nerve, intracellular chloride concentration, and other) marking a gradient of maturity toward the dopaminergic phenotype along the mitral-glomerular axis. Finally, we propose that the establishment of a synaptic contact with the olfactory nerve is the key event allowing these cells to complete their differentiation toward the DA phenotype and to reach their final destination.

A neonate with mitral stenosis due to accessory mitral valve, ventricular septal defect, and patent ductus arteriosus: changes in echocardiographical findings during the neonatal period.

PubMed

Ito, Tadahiko; Okubo, Tadashi

2002-12-01

A female neonate with mitral stenosis due to accessory mitral valve with ventricular septal defect and patent ductus arteriosus is described. She was referred to our hospital because of neonatal asphyxia. Asphyxia was improved by ventilator support, but rapid deterioration of respiration with pulmonary congestion and hemorrhage appeared 8 days after birth. Echocardiography revealed an accessory mitral valve attached to the anterior mitral leaflet with a perimembranous ventricular septal defect and patent ductus arteriosus. Although there were no echocardiographical findings indicating mitral stenosis on admission, the mitral stenosis blood flow patterns were detected by color and pulsed Doppler examination performed on the eighth day after admission. Transaortic resection of accessory mitral valve tissue was performed with patch closure of the ventricular septal defect and ligation of the ductus arteriosus 35 days after birth. After operation, pulmonary congestion and hemorrhage were improved. Postoperative echocardiography showed complete resection of the accessory mitral valve and no mitral insufficiency. We concluded that the combination of the accessory mitral valve and left-to-right shunt due to ventricular septal defect or patent ducturs arteriosus might have led to a critical hemodynamic condition due to relative mitral stenosis in the neonatal period with the decrease in pulmonary vascular resistance.

Effect of conductance linearity and multi-level cell characteristics of TaOx-based synapse device on pattern recognition accuracy of neuromorphic system

NASA Astrophysics Data System (ADS)

Sung, Changhyuck; Lim, Seokjae; Kim, Hyungjun; Kim, Taesu; Moon, Kibong; Song, Jeonghwan; Kim, Jae-Joon; Hwang, Hyunsang

2018-03-01

To improve the classification accuracy of an image data set (CIFAR-10) by using analog input voltage, synapse devices with excellent conductance linearity (CL) and multi-level cell (MLC) characteristics are required. We analyze the CL and MLC characteristics of TaOx-based filamentary resistive random access memory (RRAM) to implement the synapse device in neural network hardware. Our findings show that the number of oxygen vacancies in the filament constriction region of the RRAM directly controls the CL and MLC characteristics. By adopting a Ta electrode (instead of Ti) and the hot-forming step, we could form a dense conductive filament. As a result, a wide range of conductance levels with CL is achieved and significantly improved image classification accuracy is confirmed.

CD28-CD80 interactions control regulatory T cell motility and immunological synapse formation1,2

PubMed Central

Thauland, Timothy J.; Koguchi, Yoshinobu; Dustin, Michael L.; Parker, David C.

2014-01-01

Regulatory T cells (Tregs) are essential for tolerance to self and environmental antigens, acting in part by downmodulating costimulatory molecules on the surface of dendritic cells (DCs) and altering naïve CD4 T cell-DC interactions. Here, we show that Tregs form stable conjugates with DCs before, but not after, they decrease surface expression of the costimulatory molecule CD80 on the DCs. We use supported planar bilayers to show that Tregs dramatically slow down, but maintain a highly polarized and motile phenotype after recognizing antigen in the absence of costimulation. These motile cells are characterized by distinct accumulations of LFA-1-ICAM-1 in the lamella and TCR-MHC in the uropod, consistent with a motile immunological synapse or ‘kinapse’. However, in the presence of high, but not low, concentrations of CD80, Tregs form stationary, symmetrical synapses. Using blocking antibodies, we show that, while CTLA-4 is required for CD80 downmodulation, CD28-CD80 interactions are critical for modulating Treg motility in the presence of antigen. Together, these results support the hypothesis that Tregs are tuned to alter their motility depending on costimulatory signals. PMID:25355918

Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells

PubMed Central

Chauveau, Anne; Aucher, Anne; Eissmann, Philipp; Vivier, Eric; Davis, Daniel M.

2010-01-01

Membrane nanotubes are membranous tethers that physically link cell bodies over long distances. Here, we present evidence that nanotubes allow human natural killer (NK) cells to interact functionally with target cells over long distances. Nanotubes were formed when NK cells contacted target cells and moved apart. The frequency of nanotube formation was dependent on the number of receptor/ligand interactions and increased on NK cell activation. Most importantly, NK cell nanotubes contained a submicron scale junction where proteins accumulated, including DAP10, the signaling adaptor that associates with the activating receptor NKG2D, and MHC class I chain-related protein A (MICA), a cognate ligand for NKG2D, as occurs at close intercellular synapses between NK cells and target cells. Quantitative live-cell fluorescence imaging suggested that MICA accumulated at small nanotube synapses in sufficient numbers to trigger cell activation. In addition, tyrosine-phosphorylated proteins and Vav-1 accumulated at such junctions. Functionally, nanotubes could aid the lysis of distant target cells either directly or by moving target cells along the nanotube path into close contact for lysis via a conventional immune synapse. Target cells moving along the nanotube path were commonly polarized such that their uropods faced the direction of movement. This is the opposite polarization than for normal cell migration, implying that nanotubes can specifically drive target cell movement. Finally, target cells that remained connected to an NK cell by a nanotube were frequently lysed, whereas removing the nanotube using a micromanipulator reduced lysis of these target cells. PMID:20212116

All in the family: matrimonial mitral valve clicks.

PubMed

Desser, K B; Bokhari, S I; Benchimol, A; Romney, D

1981-05-01

Mitral valve clicks with or without late systolic murmurs were detected in genetically unrelated marital partners of 5 families. The first family represented 2 successive nonconsanguineous marital unions with 3 generations of mitral valve clicks. The second family included 1 natural and 2 adopted children with clinical and echographic evidence of mitral valve prolapse. The third family was comprised of asymptomatic parents, both with nonejection clicks and mitral valve prolapse, whose daughter presented 3 years previously with syncope, palpitations, and combined mitral and tricuspid valve prolapse. The fourth family had 3 members with auscultatory and ultrasonic manifestations of billowing mitral valve, whereas the fourth member had "silent mitral valve prolapse." The fifth family represented a mother with auscultatory and echographic evidence of mitral valve prolapse; her 14-year-old daughter had both mitral and tricuspid valve prolapse, whereas the son had a bicuspid aortic valve. Both children were products of a prior marriage, and her husband has symptomatic mitral valve prolapse. We conclude that matrimonial mitral valve prolapse probably reflects the purported (6--10%) prevalence of this disorder in the general population. The consequences of such marital union on progeny is currently unclear and warrants future investigation.

Lipid Binding Defects and Perturbed Synaptogenic Activity of a Collybistin R290H Mutant That Causes Epilepsy and Intellectual Disability*

PubMed Central

Papadopoulos, Theofilos; Schemm, Rudolf; Grubmüller, Helmut; Brose, Nils

2015-01-01

Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects—or synaptopathies—are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the CbR290H mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans. PMID:25678704

Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.

PubMed

Papadopoulos, Theofilos; Schemm, Rudolf; Grubmüller, Helmut; Brose, Nils

2015-03-27

Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects--or synaptopathies--are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the Cb(R290H) mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitation: Importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion

PubMed Central

Kubota, Kayoko; Otsuji, Yutaka; Ueno, Tetsuya; Koriyama, Chihaya; Levine, Robert A.; Sakata, Ryuzo; Tei, Chuwa

2010-01-01

Objective Diastolic subvalvular mitral leaflet tethering by left ventricular remodeling that restricts leaflet opening in the presence of annular size reduction by surgery for ischemic mitral regurgitation potentially causes functional mitral stenosis in the absence of organic leaflet lesions. Exercise, known to worsen systolic tethering and ischemic mitral regurgitation, might also dynamically exacerbate such mitral stenosis by increasing tethering. This study evaluates the mechanism and response of such mitral stenosis to exercise. Methods We measured the diastolic mitral valve area, annular area, and peak and mean transmitral pressure gradient by echocardiography in 20 healthy individuals and 31 patients who underwent surgical annuloplasty for ischemic mitral regurgitation. Results Although the mitral valve area and annular area did not significantly differ in healthy individuals (4.7 ± 0.6 cm2 vs 5.2 ± 0.6 cm2, not significant), mitral valve area was significantly smaller than the annular area in patients after annuloplasty (1.6 ± 0.2 cm2 vs 3.3 ± 0.5 cm2, P < .01). The mitral valve area was less than 1.5 cm2 only after the surgery (P < .01) and was significantly correlated with restricted leaflet opening (r2 = 0.74, P <.001), left ventricular dilatation (r2 = 0.17, P <.05), and New York Heart Association functional class (P <. 05). Exercise stress echocardiography of 12 patients demonstrated dynamic worsening in functional mitral stenosis (mitral valve area: 2.0 ± 0.5 cm2 to 1.4 ± 0.2 cm2, P < .01; mean pressure gradient: 1.5 ± 0.9 mm Hg to 6.0 ± 2.2 mm Hg, P < .01). Conclusions Persistent subvalvular leaflet tethering in the presence of annular size reduction by surgery in ischemic mitral regurgitation frequently causes functional mitral stenosis at the leaflet tip level, which is related to heart failure symptoms and can be dynamic with significant exercise-induced worsening. PMID:20122701

Thyroid hormone is required for pruning, functioning and long-term maintenance of afferent inner hair cell synapses

PubMed Central

Sundaresan, Srividya; Kong, Jee-Hyun; Fang, Qing; Salles, Felipe T.; Wangsawihardja, Felix; Ricci, Anthony J.; Mustapha, Mirna

2016-01-01

Functional maturation of afferent synaptic connections to inner hair cells (IHCs) involves pruning of excess synapses formed during development, as well as the strengthening and survival of the retained synapses. These events take place during the thyroid hormone (TH)-critical period of cochlear development, which is in the perinatal period for mice and in the third trimester for humans. Here, we used the hypothyroid Snell dwarf mouse (Pit1dw) as a model to study the role of TH in afferent type I synaptic refinement and functional maturation. We observed defects in afferent synaptic pruning and delays in calcium channel clustering in the IHCs of Pit1dw mice. Nevertheless, calcium currents and capacitance reached near normal levels in Pit1dw IHCs by the age of onset of hearing, despite the excess number of retained synapses. We restored normal synaptic pruning in Pit1dw IHCs by supplementing with TH from postnatal day (P)3 to P8, establishing this window as being critical for TH action on this process. Afferent terminals of older Pit1dw IHCs showed evidence of excitotoxic damage accompanied by a concomitant reduction in the levels of the glial glutamate transporter, GLAST. Our results indicate that a lack of TH during a critical period of inner ear development causes defects in pruning and long-term homeostatic maintenance of afferent synapses. PMID:26386265

Long-term outcome in dogs undergoing mitral valve repair with suture annuloplasty and chordae tendinae replacement.

PubMed

Mizuno, T; Mizukoshi, T; Uechi, M

2013-02-01

Mitral valve repair under cardiopulmonary bypass was performed in three dogs with clinical signs associated with mitral regurgitation that were not controlled by medication. Mitral valve repair comprised circumferential annuloplasty and chordal replacement with expanded polytetrafluoroethylene. One dog died 2 years after surgery because of severe mitral regurgitation resulting from partial circumferential suture detachment. The others survived for over 5 years, but mild mitral valve stenosis persisted in one. The replaced chordae did not rupture in any dog. Mitral valve repair appears to be an effective treatment for mitral regurgitation in dogs. Chordal replacement with expanded polytetrafluoroethylene is a feasible technique, demonstrating long-term durability in dogs. However, mitral annuloplasty techniques need improvement. © 2012 British Small Animal Veterinary Association.

Cytoneme-mediated contact-dependent transport of the Drosophila Decapentaplegic signaling protein

PubMed Central

Roy, Sougata; Huang, Hai; Liu, Songmei; Kornberg, Thomas B.

2015-01-01

Decapentaplegic (Dpp), a Drosophila morphogen signaling protein, transfers directly at synapes made at sites of contact between cells that produce Dpp and cytonemes that extend from recipient cells. The Dpp that cytonemes receive moves together with activated receptors toward the recipient cell body in motile puncta. Genetic loss-of-function conditions for diaphanous, shibire, neuroglian and capricious perturbed cytonemes by reducing their number or only the synapses they make with cells they target; and reduced cytoneme-mediated transport of Dpp and Dpp signaling. These experiments provide direct evidence that cells use cytonemes to exchange signaling proteins, that cytoneme-based exchange is essential for signaling and normal development, and that morphogen distribution and signaling can be contact-dependent, requiring cytoneme synapses. PMID:24385607

Prevention of Noise Damage to Cochlear Synapses

DTIC Science & Technology

2016-10-01

significantly less susceptible to synaptopathy than are males, suggesting that sex hormone provide protection. Second, we have shown effective protection... Sex Differences, Spiral Ganglion Neuron, Synapse, Synaptopathy 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a...Cochlea Excitotoxicity Sex Differences Glutamate Agonist Glutamate Receptor Hair Cell Hearing Threshold Noise-Induced Hearing Loss Organotypic

Activation of raphe nuclei triggers rapid and distinct effects on parallel olfactory bulb output channels

PubMed Central

Kapoor, Vikrant; Provost, Allison; Agarwal, Prateek; Murthy, Venkatesh N.

2015-01-01

The serotonergic raphe nuclei are involved in regulating brain states over time-scales of minutes and hours. We examined more rapid effects of serotonergic activation on two classes of principal neurons in the mouse olfactory bulb, mitral and tufted cells, which send olfactory information to distinct targets. Brief stimulation of the raphe nuclei led to excitation of tufted cells at rest and potentiation of their odor responses. While mitral cells at rest were also excited by raphe activation, their odor responses were bidirectionally modulated, leading to improved pattern separation of odors. In vitro whole-cell recordings revealed that specific optogenetic activation of raphe axons affected bulbar neurons through dual release of serotonin and glutamate. Therefore, the raphe nuclei, in addition to their role in neuromodulation of brain states, are also involved in fast, sub-second top-down modulation, similar to cortical feedback. This modulation can selectively and differentially sensitize or decorrelate distinct output channels. PMID:26752161

Microfluidic local perfusion chambers for the visualization and manipulation of synapses

PubMed Central

Taylor, Anne M.; Dieterich, Daniela C.; Ito, Hiroshi T.; Kim, Sally A.; Schuman, Erin M.

2010-01-01

Summary The polarized nature of neurons as well as the size and density of synapses complicates the manipulation and visualization of cell biological processes that control synaptic function. Here we developed a microfluidic local perfusion (μLP) chamber to access and manipulate synaptic regions and pre- and post-synaptic compartments in vitro. This chamber directs the formation of synapses in >100 parallel rows connecting separate neuron populations. A perfusion channel transects the parallel rows allowing access to synaptic regions with high spatial and temporal resolution. We used this chamber to investigate synapse-to-nucleus signaling. Using the calcium indicator dye, Fluo-4, we measured changes in calcium at dendrites and somata, following local perfusion of glutamate. Exploiting the high temporal resolution of the chamber, we exposed synapses to “spaced” or “massed” application of glutamate and then examined levels of pCREB in somata. Lastly, we applied the metabotropic receptor agonist, DHPG, to dendrites and observed increases in Arc transcription and Arc transcript localization. PMID:20399729

Design principles of electrical synaptic plasticity.

PubMed

O'Brien, John

2017-09-08

Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between neurons, provide rapid, bidirectional communication that accomplishes tasks distinct from and complementary to chemical synapses. These include coordination of neuron activity, suppression of voltage noise, establishment of electrical pathways that define circuits, and modulation of high order network behavior. In keeping with the omnipresent demand to alter neural network function in order to respond to environmental cues and perform tasks, electrical synapses exhibit extensive plasticity. In some networks, this plasticity can have dramatic effects that completely remodel circuits or remove the influence of certain cell types from networks. Electrical synaptic plasticity occurs on three distinct time scales, ranging from milliseconds to days, with different mechanisms accounting for each. This essay highlights principles that dictate the properties of electrical coupling within networks and the plasticity of the electrical synapses, drawing examples extensively from retinal networks. Copyright © 2017 The Author. Published by Elsevier B.V. All rights reserved.

A connectome of a learning and memory center in the adult Drosophila brain

PubMed Central

Takemura, Shin-ya; Aso, Yoshinori; Hige, Toshihide; Wong, Allan; Lu, Zhiyuan; Xu, C Shan; Rivlin, Patricia K; Hess, Harald; Zhao, Ting; Parag, Toufiq; Berg, Stuart; Huang, Gary; Katz, William; Olbris, Donald J; Plaza, Stephen; Umayam, Lowell; Aniceto, Roxanne; Chang, Lei-Ann; Lauchie, Shirley; Ogundeyi, Omotara; Ordish, Christopher; Shinomiya, Aya; Sigmund, Christopher; Takemura, Satoko; Tran, Julie; Turner, Glenn C; Rubin, Gerald M; Scheffer, Louis K

2017-01-01

Understanding memory formation, storage and retrieval requires knowledge of the underlying neuronal circuits. In Drosophila, the mushroom body (MB) is the major site of associative learning. We reconstructed the morphologies and synaptic connections of all 983 neurons within the three functional units, or compartments, that compose the adult MB’s α lobe, using a dataset of isotropic 8 nm voxels collected by focused ion-beam milling scanning electron microscopy. We found that Kenyon cells (KCs), whose sparse activity encodes sensory information, each make multiple en passant synapses to MB output neurons (MBONs) in each compartment. Some MBONs have inputs from all KCs, while others differentially sample sensory modalities. Only 6% of KC>MBON synapses receive a direct synapse from a dopaminergic neuron (DAN). We identified two unanticipated classes of synapses, KC>DAN and DAN>MBON. DAN activation produces a slow depolarization of the MBON in these DAN>MBON synapses and can weaken memory recall. DOI: http://dx.doi.org/10.7554/eLife.26975.001 PMID:28718765

The Role of Ribbons at Sensory Synapses

PubMed Central

LoGiudice, Lisamarie; Matthews, Gary

2009-01-01

Synaptic ribbons are organelles that tether vesicles at the presynaptic active zones of sensory neurons in the visual, auditory and vestibular systems. These neurons generate sustained, graded electrical signals in response to sensory stimuli, and fidelity of transmission therefore requires their synapses to release neurotransmitter continuously at high rates. It has long been thought that the ribbons at the active zones of sensory synapses accomplish this task by enhancing the size and accessibility of the readily releasable pool of synaptic vesicles, which may represent the vesicles attached to the ribbon. Recent evidence suggests that synaptic ribbons immobilize vesicles in the resting cell and coordinate the transient, synchronous release of vesicles in response to stimulation, but it is not yet clear how the ribbon can efficiently mobilize and coordinate multiple vesicles for release. However, detailed anatomical, electrophysiological and optical studies have begun to reveal the mechanics of release at ribbon synapses, and this multidisciplinary approach promises to reconcile structure, function, and mechanism at these important sensory synapses. PMID:19264728

Genetic interaction of Neuroglian and Semaphorin1a during guidance and synapse formation.

PubMed

Godenschwege, Tanja A; Murphey, Rodney K

2009-01-01

We have previously demonstrated a function for Neuroglian and Semaphorin1a in Drosophila giant fiber circuit formation. Both molecules are required for guiding the giant fibers out of the brain and have distinct functions during giant synapse formation. In this study we characterized the effects of various combinations of Neuroglian and Semaphorin1a gain and loss of function backgrounds on giant fiber circuitry formation. We found that Neuroglian and Semaphorin1a genetically interact with each other during axon guidance as well as during synapse formation. Our experiments revealed that during pathfinding of the giant fibers out of the brain, Neuroglian function seems to be dependent on Semaphorin1a. In contrast, during giant fiber synapse formation we observed that Semaphorin1a signaling as a receptor can be altered by Neuroglian in the same cell. In summary, our findings suggest that Neuroglian and Semaphorin1a can regulate each other's function in cis and that the resultant signaling output is possibly different during guidance and synapse formation.

Sequential pictorial presentation of neural interaction in the retina. 2. The depolarizing and hyperpolarizing bipolar cells at rod terminals.

PubMed

Sjöstrand, F S

2002-01-01

Each rod is connected to one depolarizing and one hyperpolarizing bipolar cell. The synaptic connections of cone processes to each bipolar cell and presynaptically to the two rod-bipolar cell synapses establishes conditions for lateral interaction at this level. Thus, the cones raise the threshold for bipolar cell depolarization which is the basis for spatial brightness contrast enhancement and consequently for high visual acuity (Sjöstrand, 2001a). The cones facilitate ganglion cell depolarization by the bipolar cells and cone input prevents horizontal cell blocking of depolarization of the depolarizing bipolar cell, extending rod vision to low illumination. The combination of reduced cone input and transient hyperpolarization of the hyperpolarizing bipolar cell at onset of a light stimulus facilitates ganglion cell depolarization extensively at onset of the stimulus while no corresponding enhancement applies to the ganglion cell response at cessation of the stimulus, possibly establishing conditions for discrimination between on- vs. off-signals in the visual centre. Reduced cone input and hyperpolarization of the hyperpolarizing bipolar cell at onset of a light stimulus accounts for Granit's (1941) 'preexcitatory inhibition'. Presynaptic inhibition maintains transmitter concentration low in the synaptic gap at rod-bipolar cell and bipolar cell-ganglion cell synapses, securing proportional and amplified postsynaptic responses at these synapses. Perfect timing of variations in facilitatory and inhibitory input to the ganglion cell confines the duration of ganglion cell depolarization at onset and at cessation of a light stimulus to that of a single synaptic transmission.

Distinct cerebellar engrams in short-term and long-term motor learning.

PubMed

Wang, Wen; Nakadate, Kazuhiko; Masugi-Tokita, Miwako; Shutoh, Fumihiro; Aziz, Wajeeha; Tarusawa, Etsuko; Lorincz, Andrea; Molnár, Elek; Kesaf, Sebnem; Li, Yun-Qing; Fukazawa, Yugo; Nagao, Soichi; Shigemoto, Ryuichi

2014-01-07

Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-term adaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short- and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.

DSCAM Localization and Function at the Mouse Cone Synapse

PubMed Central

de Andrade, Gabriel Belem; Long, Samuel S.; Fleming, Harrison; Li, Wei; Fuerst, Peter G.

2014-01-01

The Down Syndrome Cell Adhesion Molecule (DSCAM) is required for regulation of cell number, soma spacing and cell type specific dendrite avoidance in many types of retinal ganglion and amacrine cells. In this study we assay the organization of cells making up the outer plexiform layer of the retina in the absence of Dscam. Some types of OFF bipolar cells, type 3b and type 4 bipolar cells, had defects in dendrite arborization in the Dscam mutant retina, while other cell types appeared similar to wild type. The cone synapses that these cells project their dendrites to were intact, as visualized by electron microscopy, and had a distribution and density that was not significantly different than wild type. The spacing of type 3b bipolar cell dendrites was further analyzed by Voronoi domain analysis, Density Recovery Profiling (DRP) analysis and Nearest Neighbor Analysis (NNA). Spacing was found to be significantly different when comparing wild type and mutant type 3b bipolar cell dendrites. Defects in arborization of these bipolar cells could not be attributed to the disorganization of inner plexiform layer cells that occurs in the Dscam mutant retina or an increase in cell number, as they arborized when Dscam was targeted in retinal ganglion cells only or in the bax null retina. Localization of DSCAM was assayed and the protein was localized near to cone synapses in mouse, macaque and ground squirrel retinas. DSCAM protein was detected in several types of bipolar cells, including type 3b and type 4 bipolar cells. PMID:24477985

Heart valve replacement with the Sorin tilting-disc prosthesis. A 10-year experience.

PubMed

Milano, A; Bortolotti, U; Mazzucco, A; Mossuto, E; Testolin, L; Thiene, G; Gallucci, V

1992-02-01

From 1978 to 1988, 697 patients with a mean age of 48 +/- 11 years (range 5 to 75 years) received a Sorin tilting-disc prosthesis; 358 had had aortic valve replacement, 247 mitral valve replacement, and 92 mitral and aortic valve replacement. Operative mortality rates were 7.8%, 11.3%, and 10.8%, respectively, in the three groups. Cumulative duration of follow-up is 1650 patient-years for aortic valve replacement (maximum follow-up 11.4 years), 963 patient-years for mitral valve replacement (maximum follow-up 9.9 years) and 328 patient-years for mitral and aortic valve replacement (maximum follow-up 9.4 years). Actuarial survival at 9 years is 72% +/- 4% after mitral valve replacement, 70% +/- 3% after aortic valve replacement, and 50% +/- 12% after mitral and aortic valve replacement, and actuarial freedom from valve-related deaths is 97% +/- 2% after mitral valve replacement, 92% +/- 2% after aortic valve replacement, and 62% +/- 15% after mitral and aortic valve replacement. Thromboembolic events occurred in 21 patients with aortic valve replacement (1.3% +/- 0.2%/pt-yr), in 12 with mitral valve replacement (1.2% +/- 0.3% pt-yr), and in seven with mitral and aortic valve replacement (2.1% +/- 0.8%), with one case of prosthetic thrombosis in each group; actuarial freedom from thromboembolism at 9 years is 92% +/- 3% after mitral valve replacement, 91% +/- 3% after aortic valve replacement, and 74% +/- 16% after mitral and aortic valve replacement. Anticoagulant-related hemorrhage was observed in 15 patients after aortic valve replacement (0.9% +/- 0.2%/pt-yr), in 9 after mitral valve replacement (0.9% +/- 0.3%/pt-yr), and in 6 with mitral and aortic valve replacement (0.9% +/- 0.5%/pt-yr); actuarial freedom from this complication at 9 years is 94% +/- 2% after aortic valve replacement, 91% +/- 4% after mitral valve replacement, and 68% +/- 16% after mitral and aortic valve replacement. Actuarial freedom from reoperation at 9 years is 97% +/- 2% after mitral and aortic valve replacement, 92% +/- 4% after mitral valve replacement, and 89% +/- 3% after aortic valve replacement, with no cases of mechanical fracture. The Sorin valve has shown a satisfactory long-term overall performance, comparable with other mechanical prostheses, and an excellent durability that renders it a reliable heart valve substitute for the mitral and aortic positions.

Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model

PubMed Central

Luque, Niceto R.; Garrido, Jesús A.; Naveros, Francisco; Carrillo, Richard R.; D'Angelo, Egidio; Ros, Eduardo

2016-01-01

Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing-dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep-cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID:26973504

Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation.

PubMed

Fogel, Adam I; Stagi, Massimiliano; Perez de Arce, Karen; Biederer, Thomas

2011-09-16

Synapses are specialized adhesion sites between neurons that are connected by protein complexes spanning the synaptic cleft. These trans-synaptic interactions can organize synapse formation, but their macromolecular properties and effects on synaptic morphology remain incompletely understood. Here, we demonstrate that the synaptic cell adhesion molecule SynCAM 1 self-assembles laterally via its extracellular, membrane-proximal immunoglobulin (Ig) domains 2 and 3. This cis oligomerization generates SynCAM oligomers with increased adhesive capacity and instructs the interactions of this molecule across the nascent and mature synaptic cleft. In immature neurons, cis assembly promotes the adhesive clustering of SynCAM 1 at new axo-dendritic contacts. Interfering with the lateral self-assembly of SynCAM 1 in differentiating neurons strongly impairs its synaptogenic activity. At later stages, the lateral oligomerization of SynCAM 1 restricts synaptic size, indicating that this adhesion molecule contributes to the structural organization of synapses. These results support that lateral interactions assemble SynCAM complexes within the synaptic cleft to promote synapse induction and modulate their structure. These findings provide novel insights into synapse development and the adhesive mechanisms of Ig superfamily members.

Cellular Distribution and Subcellular Localization of Molecular Components of Vesicular Transmitter Release in Horizontal Cells of Rabbit Retina

PubMed Central

HIRANO, ARLENE A.; BRANDSTÄTTER, JOHANN H.; BRECHA, NICHOLAS C.

2010-01-01

The mechanism underlying transmitter release from retinal horizontal cells is poorly understood. We investigated the possibility of vesicular transmitter release from mammalian horizontal cells by examining the expression of synaptic proteins that participate in vesicular transmitter release at chemical synapses. Using immunocytochemistry, we evaluated the cellular and subcellular distribution of complexin I/II, syntaxin-1, and synapsin I in rabbit retina. Strong labeling for complexin I/II, proteins that regulate a late step in vesicular transmitter release, was found in both synaptic layers of the retina, and in somata of A- and B-type horizontal cells, of γ-aminobutyric acid (GABA)- and glycinergic amacrine cells, and of ganglion cells. Immunoelectron microscopy demonstrated the presence of complexin I/II in horizontal cell processes postsynaptic to rod and cone ribbon synapses. Syntaxin-1, a core protein of the soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) complex known to bind to complexin, and synapsin I, a synaptic vesicle-associated protein involved in the Ca2+-dependent recruitment of synaptic vesicles for transmitter release, were also present in the horizontal cells and their processes at photoreceptor synapses. Photoreceptors and bipolar cells did not express any of these proteins at their axon terminals. The presence of complexin I/II, syntaxin-1, and synapsin I in rabbit horizontal cell processes and tips suggests that a vesicular mechanism may underlie transmitter release from mammalian horizontal cells. PMID:15912504

Improved mitral valve coaptation and reduced mitral valve annular size after percutaneous mitral valve repair (PMVR) using the MitraClip system.

PubMed

Patzelt, Johannes; Zhang, Yingying; Magunia, Harry; Ulrich, Miriam; Jorbenadze, Rezo; Droppa, Michal; Zhang, Wenzhong; Lausberg, Henning; Walker, Tobias; Rosenberger, Peter; Seizer, Peter; Gawaz, Meinrad; Langer, Harald F

2017-08-01

Improved mitral valve leaflet coaptation with consecutive reduction of mitral regurgitation (MR) is a central goal of percutaneous mitral valve repair (PMVR) with the MitraClip® system. As influences of PMVR on mitral valve geometry have been suggested before, we examined the effect of the procedure on mitral annular size in relation to procedural outcome. Geometry of the mitral valve annulus was evaluated in 183 patients undergoing PMVR using echocardiography before and after the procedure and at follow-up. Mitral valve annular anterior-posterior (ap) diameter decreased from 34.0 ± 4.3 to 31.3 ± 4.9 mm (P < 0.001), and medio-lateral (ml) diameter from 33.2 ± 4.8 to 32.4 ± 4.9 mm (P < 0.001). Accordingly, we observed an increase in MV leaflet coaptation after PMVR. The reduction of mitral valve ap diameter showed a significant inverse correlation with residual MR. Importantly, the reduction of mitral valve ap diameter persisted at follow-up (31.3 ± 4.9 mm post PMVR, 28.4 ± 5.3 mm at follow-up). This study demonstrates mechanical approximation of both mitral valve annulus edges with improved mitral valve annular coaptation by PMVR using the MitraClip® system, which correlates with residual MR in patients with MR. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Preparation of Horizontal Slices of Adult Mouse Retina for Electrophysiological Studies.

PubMed

Feigenspan, Andreas; Babai, Norbert Zsolt

2017-01-27

Vertical slice preparations are well established to study circuitry and signal transmission in the adult mammalian retina. The plane of sectioning in these preparations is perpendicular to the retinal surface, making it ideal for the study of radially oriented neurons like photoreceptors and bipolar cells. However, the large dendritic arbors of horizontal cells, wide-field amacrine cells, and ganglion cells are mostly truncated, leaving markedly reduced synaptic activity in these cells. Whereas ganglion cells and displaced amacrine cells can be studied in a whole-mounted preparation of the retina, horizontal cells and amacrine cells located in the inner nuclear layer are only poorly accessible for electrodes in whole retina tissue. To achieve maximum accessibility and synaptic integrity, we developed a horizontal slice preparation of the mouse retina, and studied signal transmission at the synapse between photoreceptors and horizontal cells. Horizontal sectioning allows (1) easy and unambiguous visual identification of horizontal cell bodies for electrode targeting, and (2) preservation of the extended horizontal cell dendritic fields, as a prerequisite for intact and functional cone synaptic input to horizontal cell dendrites. Horizontal cells from horizontal slices exhibited tonic synaptic activity in the dark, and they responded to brief flashes of light with a reduction of inward current and diminished synaptic activity. Immunocytochemical evidence indicates that almost all cones within the dendritic field of a horizontal cell establish synapses with its peripheral dendrites. The horizontal slice preparation is therefore well suited to study the physiological properties of horizontally extended retinal neurons as well as sensory signal transmission and integration across selected synapses.

Congenital uni-leaflet mitral valve with severe stenosis: A case report with literature review.

PubMed

Zhang, Weixin; Wang, Yonghuai; Ma, Chunyan; Zhang, Zhiwei; Yang, Jun

2017-03-01

Numerical abnormalities of mitral leaflets is a special entity in congenital mitral malformations. Previously reported cases of uni-leaflet mitral valve were primarily related to absence or dysplasia of certain leaflets. We present a case here with mitral leaflets that were not divided into anterior and posterior as usual, but developed as an integral structure instead, which is different from previously documented cases of uni-leaflet mitral valves. Real time three-dimensional echocardiography (RT3DE) provides a visual presentation of the abnormal mitral structure which was confirmed by surgical operation. To the best of our knowledge, this unusual form of uni-leaflet mitral valve has not been reported yet. © 2017, Wiley Periodicals, Inc.

Ribbon synapses compute temporal contrast and encode luminance in retinal rod bipolar cells

PubMed Central

Oesch, Nicholas W.; Diamond, Jeffrey S.

2011-01-01

Contrast is computed throughout the nervous system to encode changing inputs efficiently. The retina encodes luminance and contrast over a wide range of visual conditions and so must adapt its responses to maintain sensitivity and avoid saturation. Here we show how one type of adaptation allows individual synapses to compute contrast and encode luminance in biphasic responses to step changes in light levels. Light-evoked depletion of the readily releasable vesicle pool (RRP) at rod bipolar cell (RBC) ribbon synapses in rat retina limits the dynamic range available to encode transient but not sustained responses, thereby allowing the transient and sustained components of release to compute temporal contrast and encode mean light levels, respectively. A release/replenishment model shows that a single, homogeneous pool of synaptic vesicles is sufficient to generate this behavior and reveals that the dominant mechanism shaping the biphasic contrast/luminance response is the partial depletion of the RRP. PMID:22019730

Microorganism and filamentous fungi drive evolution of plant synapses

PubMed Central

Baluška, František; Mancuso, Stefano

2013-01-01

In the course of plant evolution, there is an obvious trend toward an increased complexity of plant bodies, as well as an increased sophistication of plant behavior and communication. Phenotypic plasticity of plants is based on the polar auxin transport machinery that is directly linked with plant sensory systems impinging on plant behavior and adaptive responses. Similar to the emergence and evolution of eukaryotic cells, evolution of land plants was also shaped and driven by infective and symbiotic microorganisms. These microorganisms are the driving force behind the evolution of plant synapses and other neuronal aspects of higher plants; this is especially pronounced in the root apices. Plant synapses allow synaptic cell–cell communication and coordination in plants, as well as sensory-motor integration in root apices searching for water and mineral nutrition. These neuronal aspects of higher plants are closely linked with their unique ability to adapt to environmental changes. PMID:23967407

Axonal synapse sorting in medial entorhinal cortex

NASA Astrophysics Data System (ADS)

Schmidt, Helene; Gour, Anjali; Straehle, Jakob; Boergens, Kevin M.; Brecht, Michael; Helmstaedter, Moritz

2017-09-01

Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges.

Depression-Biased Reverse Plasticity Rule Is Required for Stable Learning at Top-Down Connections

PubMed Central

Burbank, Kendra S.; Kreiman, Gabriel

2012-01-01

Top-down synapses are ubiquitous throughout neocortex and play a central role in cognition, yet little is known about their development and specificity. During sensory experience, lower neocortical areas are activated before higher ones, causing top-down synapses to experience a preponderance of post-synaptic activity preceding pre-synaptic activity. This timing pattern is the opposite of that experienced by bottom-up synapses, which suggests that different versions of spike-timing dependent synaptic plasticity (STDP) rules may be required at top-down synapses. We consider a two-layer neural network model and investigate which STDP rules can lead to a distribution of top-down synaptic weights that is stable, diverse and avoids strong loops. We introduce a temporally reversed rule (rSTDP) where top-down synapses are potentiated if post-synaptic activity precedes pre-synaptic activity. Combining analytical work and integrate-and-fire simulations, we show that only depression-biased rSTDP (and not classical STDP) produces stable and diverse top-down weights. The conclusions did not change upon addition of homeostatic mechanisms, multiplicative STDP rules or weak external input to the top neurons. Our prediction for rSTDP at top-down synapses, which are distally located, is supported by recent neurophysiological evidence showing the existence of temporally reversed STDP in synapses that are distal to the post-synaptic cell body. PMID:22396630

Transcatheter mitral valve repair in osteogenesis imperfecta associated mitral valve regurgitation.

PubMed

van der Kley, Frank; Delgado, Victoria; Ajmone Marsan, Nina; Schalij, Martin J

2014-08-01

Osteogenesis imperfecta is associated with increased prevalence of significant mitral valve regurgitation. Surgical mitral valve repair and replacement are feasible but are associated with increased risk of bleeding and dehiscence of implanted valves may occur more frequently. The present case report describes the outcomes of transcatheter mitral valve repair in a patient with osteogenesis imperfecta. A 60 year-old patient with osteogenesis imperfecta and associated symptomatic moderate to severe mitral regurgitation underwent transthoracic echocardiography which showed a nondilated left ventricle with preserved systolic function and moderate to severe mitral regurgitation. On transoesophageal echocardiography the regurgitant jet originated between the anterolateral scallops of the anterior and posterior leaflets (A1-P1). Considering the comorbidities associated with osteogenesis imperfecta the patient was accepted for transcatheter mitral valve repair using the Mitraclip device (Abbott vascular, Menlo, CA). Under fluoroscopy and 3D transoesophageal echocardiography guidance, a Mitraclip device was implanted between the anterolateral and central scallops with significant reduction of mitral regurgitation. The postoperative evolution was uneventful. At one month follow-up, transthoracic echocardiography showed a stable position of the Mitraclip device with no mitral regurgitation. Transcatheter mitral valve repair is feasible and safe in patients with osteogenesis imperfecta and associated symptomatic significant mitral regurgitation. Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Relation of Mitral Valve Surgery Volume to Repair Rate, Durability, and Survival.

PubMed

Chikwe, Joanna; Toyoda, Nana; Anyanwu, Anelechi C; Itagaki, Shinobu; Egorova, Natalia N; Boateng, Percy; El-Eshmawi, Ahmed; Adams, David H

2017-04-24

Degenerative mitral valve repair rates remain highly variable, despite established benefits of repair over replacement. The contribution of surgeon-specific factors is poorly defined. This study evaluated the influence of surgeon case volume on degenerative mitral valve repair rates and outcomes. A mandatory New York State database was queried and 5,475 patients were identified with degenerative mitral disease who underwent mitral valve operations between 2002 and 2013. Mitral repair rates, mitral reoperations within 12 months of repair, and survival were analyzed using multivariable Cox modeling and restricted cubic spline function. Median annual surgeon volume of any mitral operations was 10 (range 1 to 230), with a mean repair rate of 55% (n = 20,797 of 38,128). In the subgroup of patients with degenerative disease, the mean repair rate was 67% (n = 3,660 of 5,475), with a range of 0% to 100%. Mean repair rates ranged from 48% (n = 179 of 370) for surgeons with total annual volumes of ≤10 mitral operations to 77% (n = 1,710 of 2,216) for surgeons with total annual volumes of >50 mitral operations (p < 0.001). Higher total annual surgeon volume was associated with increased repair rates of degenerative mitral valve disease (adjusted odds ratio [OR]: 1.13 for every additional 10 mitral operations; 95% confidence interval [CI]: 1.10 to 1.17; p < 0.001); a steady decrease in reoperation risk until 25 total mitral operations annually; and improved 1-year survival (adjusted hazard ratio: 0.95 for every additional 10 operations; 95% CI: 0.92 to 0.98; p = 0.001). For surgeons with a total annual volume of ≤25 mitral operations, repair rates were higher (63.8%; n = 180 of 282) if they operated in the same institution as a surgeon with total annual mitral volumes of >50 and degenerative mitral valve repair rates of >70%, compared with surgeons operating in the other institutions (51.3%; n = 580 of 1,130) (adjusted OR: 1.79; 95% CI: 1.24 to 2.60; p < 0.001). This study suggests that individual surgeon volume is a determinant of not only mitral repair rates, but also freedom from reoperation, and survival. The data from this study support the guideline's concept of reference referral to experienced mitral surgeons to improve outcomes in patients with degenerative mitral valve disease. Copyright © 2017. Published by Elsevier Inc.

Repair for mitral stenosis due to pannus formation after Duran ring annuloplasty.

PubMed

Song, Seunghwan; Cho, Seong Ho; Yang, Ji-Hyuk; Park, Pyo Won

2010-12-01

Mitral stenosis after mitral repair with using an annuloplasty ring is not common and it is almost always due to pannus formation. Mitral valve replacement was required in most of the previous cases of pannus covering the mitral valve leaflet, which could not be stripped off without damaging the valve leaflets. In two cases, we removed the previous annuloplasty ring and pannus without leaflet injury, and we successfully repaired the mitral valve. During the follow-up of 4 months and 39 months respectively, we observed improvement of the patients' symptoms and good valvular function. Redo mitral repair may be a possible method for treating mitral stenosis due to pannus formation after ring annuloplasty. Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

The lipid habitats of neurotransmitter receptors in brain.

PubMed

Borroni, María Virginia; Vallés, Ana Sofía; Barrantes, Francisco J

2016-11-01

Neurotransmitter receptors, the macromolecules specialized in decoding the chemical signals encrypted in the chemical signaling mechanism in the nervous system, occur either at the somatic cell surface of chemically excitable cells or at specialized subcellular structures, the synapses. Synapses have lipid compositions distinct from the rest of the cell membrane, suggesting that neurotransmitter receptors and their scaffolding and adaptor protein partners require specific lipid habitats for optimal operation. In this review we discuss some paradigmatic cases of neurotransmitter receptor-lipid interactions, highlighting the chemical nature of the intervening lipid species and providing examples of the receptor mechanisms affected by interaction with lipids. The focus is on the effects of cholesterol, glycerophospholipids and covalent fatty acid acylation on neurotransmitter receptors. We also briefly discuss the role of lipid phase states involving lateral heterogeneities of the host membrane known to modulate membrane transport, protein sorting and signaling. Modulation of neurotransmitter receptors by lipids occurs at multiple levels, affecting a wide span of activities including their trafficking, sorting, stability, residence lifetime at the cell surface, endocytosis, and recycling, among other important functional properties at the synapse. Copyright © 2016 Elsevier B.V. All rights reserved.

Synaptogenesis Is Modulated by Heparan Sulfate in Caenorhabditis elegans

PubMed Central

Lázaro-Peña, María I.; Díaz-Balzac, Carlos A.; Bülow, Hannes E.; Emmons, Scott W.

2018-01-01

The nervous system regulates complex behaviors through a network of neurons interconnected by synapses. How specific synaptic connections are genetically determined is still unclear. Male mating is the most complex behavior in Caenorhabditis elegans. It is composed of sequential steps that are governed by > 3000 chemical connections. Here, we show that heparan sulfates (HS) play a role in the formation and function of the male neural network. HS, sulfated in position 3 by the HS modification enzyme HST-3.1/HS 3-O-sulfotransferase and attached to the HS proteoglycan glypicans LON-2/glypican and GPN-1/glypican, functions cell-autonomously and nonautonomously for response to hermaphrodite contact during mating. Loss of 3-O sulfation resulted in the presynaptic accumulation of RAB-3, a molecule that localizes to synaptic vesicles, and disrupted the formation of synapses in a component of the mating circuits. We also show that the neural cell adhesion protein NRX-1/neurexin promotes and the neural cell adhesion protein NLG-1/neuroligin inhibits the formation of the same set of synapses in a parallel pathway. Thus, neural cell adhesion proteins and extracellular matrix components act together in the formation of synaptic connections. PMID:29559501

Transcatheter mitral direct annuloplasty: state of the art.

PubMed

Maisano, F; Kuck, K H

2014-06-01

Transcatheter mitral interventions are emerging as a novel therapy for patients with severe symptomatic mitral regurgitation who are deemed to be high risk or inoperable. Surgical treatment of mitral regurgitation includes a wide spectrum of therapies, ranging from leaflet and annular repair, to mitral valve replacement. Annuloplasty plays a fundamental role in open heart mitral valve repair, since it is associated with longer durability and higher degree of mitral regurgitation reduction. Direct annuloplasty is the interventional methodology most closely reproducing open heart annular repair. We describe the challenges and opportunities of the most promising technologies currently under development which will become available in clinical practice in the next future.

Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity.

PubMed

Nietz, Angela K; Vaden, Jada H; Coddington, Luke T; Overstreet-Wadiche, Linda; Wadiche, Jacques I

2017-10-13

Golgi cells are the principal inhibitory neurons at the input stage of the cerebellum, providing feedforward and feedback inhibition through mossy fiber and parallel fiber synapses. In vivo studies have shown that Golgi cell activity is regulated by climbing fiber stimulation, yet there is little functional or anatomical evidence for synapses between climbing fibers and Golgi cells. Here, we show that glutamate released from climbing fibers activates ionotropic and metabotropic receptors on Golgi cells through spillover-mediated transmission. The interplay of excitatory and inhibitory conductances provides flexible control over Golgi cell spiking, allowing either excitation or a biphasic sequence of excitation and inhibition following single climbing fiber stimulation. Together with prior studies of spillover transmission to molecular layer interneurons, these results reveal that climbing fibers exert control over inhibition at both the input and output layers of the cerebellar cortex.

Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber-Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex.

PubMed

Wang, Yuan; Dong, Jing; Wang, Yi; Wei, Wei; Song, Binbin; Shan, Zhongyan; Teng, Weiping; Chen, Jie

2016-10-01

Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber-Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.

Mitral valve prolapse and hyperthyroidism: effect of patient selection.

PubMed

Zullo, M A; Devereux, R B; Kramer-Fox, R; Lutas, E M; Brown, W T

1985-11-01

Patients with mitral valve prolapse and hyperthyroidism have common symptoms; the most outstanding symptom is palpitation. To determine whether or not common symptoms contributed to the reported association of these conditions, we evaluated 220 patients with symptomatic mitral valve prolapse and 216 first-degree relatives in 72 families; 65 relatives with mitral valve prolapse and 151 relatives without mitral valve prolapse, all greater than or equal to 16 years of age. Thirty subjects, aged 49 +/- 13 years (p less than 0.025 vs entire study group), had thyroid disease (23 subjects had definite thyroid disease, seven subjects had probable); 27 of 30 subjects with thyroid disease (90%) were female (p less than 0.005). The age- and sex-adjusted prevalence of hyperthyroidism was significantly higher in probands with mitral valve prolapse than in family members without mitral valve prolapse (3.5% vs 0%, p = 0.03), while an intermediate prevalence of hyperthyroidism (2.2%) was observed in family members with mitral valve prolapse. Thus, the prevalence of hyperthyroidism is increased among symptomatic patients with mitral valve prolapse as compared to family members without mitral valve prolapse, but the prevalence of thyroid conditions is similar among family members with or without this condition. These findings are explained by the effect of common symptoms on clinical detection of both mitral valve prolapse and hyperthyroidism.

Mitral Valve Repair Using ePTFE Sutures for Ruptured Mitral Chordae Tendineae: A Computational Simulation Study

PubMed Central

Rim, Yonghoon; Laing, Susan T.; McPherson, David D.; Kim, Hyunggun

2013-01-01

Mitral valve repair using expanded polytetrafluoroethylene (ePTFE) sutures is an established and preferred interventional method to resolve the complex pathophysiologic problems associated with chordal rupture. We developed a novel computational evaluation protocol to determine the effect of the artificial sutures on restoring mitral valve function following valve repair. A virtual mitral valve was created using three-dimensional echocardiographic data in a patient with ruptured mitral chordae tendineae. Virtual repairs were designed by adding artificial sutures between the papillary muscles and the posterior leaflet where the native chordae were ruptured. Dynamic finite element simulations were performed to evaluate pre- and post-repair mitral valve function. Abnormal posterior leaflet prolapse and mitral regurgitation was clearly demonstrated in the mitral valve with ruptured chordae. Following virtual repair to reconstruct ruptured chordae, the severity of the posterior leaflet prolapse decreased and stress concentration was markedly reduced both in the leaflet tissue and the intact native chordae. Complete leaflet coaptation was restored when four or six sutures were utilized. Computational simulations provided quantitative information of functional improvement following mitral valve repair. This novel simulation strategy may provide a powerful tool for evaluation and prediction of interventional treatment for ruptured mitral chordae tendineae. PMID:24072489

Synaptic Basis for Whisker Deprivation-Induced Synaptic Depression in Rat Somatosensory Cortex

PubMed Central

Bender, Kevin J.; Allen, Cara B.; Bender, Vanessa A.; Feldman, Daniel E.

2011-01-01

Whisker deprivation weakens excitatory layer 4 (L4) inputs to L2/3 pyramidal cells in rat primary somatosensory (S1) cortex, which is likely to contribute to whisker map plasticity. This weakening has been proposed to represent long-term depression (LTD) induced by sensory deprivation in vivo. Here, we studied the synaptic expression mechanisms for deprivation-induced weakening of L4-L2/3 inputs and assessed its similarity to LTD, which is known to be expressed presynaptically at L4-L2/3 synapses. Whisker deprivation increased the paired pulse ratio at L4-L2/3 synapses and slowed the use-dependent block of NMDA receptor currents by MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], indicating that deprivation reduced transmitter release probability at these synapses. In contrast, deprivation did not alter either miniature EPSC amplitude in L2/3 neurons or the amplitude of quantal L4-L2/3 synaptic responses measured in strontium, indicating that postsynaptic responsiveness was unchanged. In young postnatal day 12 (P12) rats, at least 4 d of deprivation were required to significantly weaken L4-L2/3 synapses. Similar weakening occurred when deprivation began at older ages (P20), when synapses are mostly mature, indicating that weakening is unlikely to represent a failure of synaptic maturation but instead represents a reduction in the strength of existing synapses. Thus, whisker deprivation weakens L4-L2/3 synapses by decreasing presynaptic function, similar to known LTD mechanisms at this synapse. PMID:16624936

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse.

PubMed

Huang, Yu; Chen, Zhiying; Jang, Joon Hee; Baig, Mirza S; Bertolet, Grant; Schroeder, Casey; Huang, Shengjian; Hu, Qian; Zhao, Yong; Lewis, Dorothy E; Qin, Lidong; Zhu, Michael Xi; Liu, Dongfang

2018-04-18

The inhibitory receptor programmed cell death protein 1 (PD-1) is upregulated on a variety of immune cells, including natural killer (NK) cells, during chronic viral infection and tumorigenesis. Blockade of PD-1 or its ligands produces durable clinical responses with tolerable side effects in patients with a broad spectrum of cancers. However, the underlying molecular mechanisms of how PD-1 regulates NK cell function remain poorly characterized. We sought to determine the effect of PD-1 signaling on NK cells. PD-1 was overexpressed in CD16-KHYG-1 (a human NK cell line with both antibody-dependent cellular cytotoxicity through CD16 and natural cytotoxicity through NKG2D) cells and stimulated by exposing the cells to NK-sensitive target cells expressing programmed death ligand 1 (PD-L1). PD-1 engagement by PD-L1 specifically blocked NK cell-mediated cytotoxicity without interfering with the conjugation between NK cells and target cells. Further examination showed that PD-1 signaling blocked lytic granule polarization in NK cells, which was accompanied by failure of integrin-linked kinase, a key molecule in the integrin outside-in signaling pathway, to accumulate in the immunological synapse after NK-target cell conjugation. Our results suggest that NK cell cytotoxicity is inhibited by PD-1 engagement, which blocks lytic granule polarization to the NK cell immunological synapse with concomitant impairment of integrin outside-in signaling. This study provides novel mechanistic insights into how PD-1 inhibition disrupts NK cell function. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Mitral stenosis (image)

MedlinePlus

Mitral stenosis is a heart valve disorder that narrows or obstructs the mitral valve opening. Narrowing of the ... to the body. The main risk factor for mitral stenosis is a history of rheumatic fever but it ...

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

PubMed Central

Goutman, Juan D; Auclair, Sarah Marie; Boutet de Monvel, Jacques; Tertrais, Margot; Emptoz, Alice; Parrin, Alexandre; Nouaille, Sylvie; Guillon, Marc; Sachse, Martin; Ciric, Danica; Bahloul, Amel; Hardelin, Jean-Pierre; Sutton, Roger Bryan; Avan, Paul; Krishnakumar, Shyam S; Rothman, James E

2017-01-01

Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone. PMID:29111973

Feed-back modulation of cone synapses by L-horizontal cells of turtle retina.

PubMed

Gerschenfeld, H M; Piccolino, M; Neyton, J

1980-12-01

Light stimulation of the periphery of the receptive field of turtle cones can evoke both transient and sustained increases of the cone Ca2+ conductance, which may become regenerative. Such increase in the cone Ca2+ conductance evoked by peripheral illumination results from the activation of a polysynaptic pathway involving a feed-back connexion from the L-horizontal cells (L-HC) to the cones. Thus the hyperpolarization of a L-HC by inward current injection can evoke a Ca2+ conductance increase in neighbouring cones. The cone Ca2+ channels thus activated are likely located at its synaptic endings and probably intervene in the cone transmitter release. Therefore the feed-back connexion between L-HC and cones by modifying the Ca2+ conductance of cones could actually modulate the transmitter release from cone synapses. Such feed-back modulation of cone synapses plays a role in the organization of the colour-coded responses of the chromaticity type-horizontal cells and probably of other second order neurones, post-synaptic to the cones. The mechanisms operating the feed-back connexion from L-HC to cones are discussed.

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses.

PubMed

Michalski, Nicolas; Goutman, Juan D; Auclair, Sarah Marie; Boutet de Monvel, Jacques; Tertrais, Margot; Emptoz, Alice; Parrin, Alexandre; Nouaille, Sylvie; Guillon, Marc; Sachse, Martin; Ciric, Danica; Bahloul, Amel; Hardelin, Jean-Pierre; Sutton, Roger Bryan; Avan, Paul; Krishnakumar, Shyam S; Rothman, James E; Dulon, Didier; Safieddine, Saaid; Petit, Christine

2017-11-07

Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C 2 -domain, Ca 2+ -binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice ( Otof Ala515,Ala517/Ala515,Ala517 ) with lower Ca 2+ -binding affinity of the C 2 C domain. The IHC ribbon synapse structure, synaptic Ca 2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca 2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca 2+ concentration, by varying Ca 2+ influx through voltage-gated Ca 2+ -channels or Ca 2+ uncaging. Otoferlin thus functions as a Ca 2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone.

The inability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses

PubMed Central

Arhel, Nathalie; Lehmann, Martin; Clauß, Karen; Nienhaus, G. Ulrich; Piguet, Vincent; Kirchhoff, Frank

2009-01-01

Viruses that infect T cells, including those of the lentivirus genus, such as HIV-1, modulate the responsiveness of infected T cells to stimulation by interacting APCs in a manner that renders the T cells more permissive for viral replication. HIV-1 and other primate lentiviruses use their Nef proteins to manipulate the T cell/APC contact zone, the immunological synapse (IS). It is known that primate lentiviral Nef proteins differ substantially in their ability to modulate cell surface expression of the TCR-CD3 and CD28 receptors critical for the formation and function of the IS. However, the impact of these differences in Nef function on the interaction and communication between virally infected T cells and primary APCs has not been investigated. Here we have used primary human cells to show that Nef proteins encoded by HIV-2 and most SIVs, which downmodulate cell surface expression of TCR-CD3, disrupt formation of the IS between infected T cells and Ag-presenting macrophages or DCs. In contrast, nef alleles from HIV-1 and its simian precursor SIVcpz failed to suppress synapse formation and events downstream of TCR signaling. Our data suggest that most primate lentiviruses disrupt communication between virally infected CD4+ Th cells and APCs, whereas HIV-1 and its SIV precursor have largely lost this capability. The resulting differences in the levels of T cell activation and apoptosis may play a role in the pathogenesis of AIDS. PMID:19759518

Functional and molecular alterations in T Cells induced by CCL5.

PubMed

Cridge, T J; Horowitz, K M; Marinucci, M N; Rose, K M; Wells, M; Werner, M T; Kurt, Robert A

2006-01-01

To delineate whether, and the extent to which, CCL5 could impact T cell function we examined cytokine production and proliferative ability following CCL5 treatment in vitro. We report a decreased ability of splenic T cells to produce IFN-? and TNF-a as well as proliferate in response to crosslinking with antibody to CD3 after 72, but not 24 hours of CCL5 exposure. To identify a mechanism by which CCL5 modulated T cell function, we examined T cell receptor translocation and lipid raft clustering. After exposure to CCL5, T cells were less efficient at translocating the TCR and clustering lipid rafts. Since TCR translocation and lipid raft clustering are required for creation of an immunological synapse, these data suggest that extended exposure to CCL5 may impact T cell effector function by modulating the ability to create a functional immunological synapse.

Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer’s disease

PubMed Central

Berchtold, Nicole C.; Coleman, Paul D.; Cribbs, David H.; Rogers, Joseph; Gillen, Daniel L.; Cotman, Carl W.

2014-01-01

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD. PMID:23273601

Genetic Interaction of Neuroglian and Semaphorin1a during Guidance and Synapse Formation

PubMed Central

Godenschwege, Tanja A.; Murphey, Rodney K.

2009-01-01

We have previously demonstrated a function for Neuroglian and Semaphorin1a in Drosophila giant fiber circuit formation. Both molecules are required for guiding the giant fibers out of the brain and have distinct functions during giant synapse formation. In this study we characterized the effects of various combinations of Neuroglian and Semaphorin1a gain and loss of function backgrounds on giant fiber circuitry formation. We found that Neuroglian and Semaphorin1a genetically interact with each other during axon guidance as well as during synapse formation. Our experiments revealed that during pathfinding of the giant fibers out of the brain, Neuroglian function seems to be dependent on Semaphorin1a. In contrast, during giant fiber synapse formation we observed that Semaphorin1a signaling as a receptor can be altered by Neuroglian in the same cell. In summary, our findings suggest that Neuroglian and Semaphorin1a can regulate each other’s function in cis and that the resultant signaling output is possibly different during guidance and synapse formation. PMID:19052954

Percutaneous transfemoral-transseptal implantation of a second-generation CardiAQ mitral valve bioprosthesis: first procedure description and 30-day follow-up.

PubMed

Ussia, Gian Paolo; Quadri, Arshad; Cammalleri, Valeria; De Vico, Pasquale; Muscoli, Saverio; Marchei, Massimo; Ruvolo, Giovanni; Sondergaard, Lars; Romeo, Francesco

2016-02-01

Transcatheter mitral valve implantation for mitral valve regurgitation is in the very early phase of development because of challenging anatomy and device dimensions. We describe the procedure of a transfemoral-transseptal implantation of the second-generation CardiAQ mitral valve bioprosthesis and 30-day follow-up. The procedure was performed percutaneously, without any left extracorporeal circulatory support. The patient had severe mitral regurgitation with severely depressed ventricular function and other comorbidities. The patient was deemed extreme high risk for conventional cardiac surgery by a multidisciplinary team. The main procedural steps were the creation of an arteriovenous loop with an exchange nitinol wire, and the use of a customised "steerable snare system" to facilitate the catheter delivery system into the mitral annulus. Transoesophageal echocardiography and fluoroscopy were utilised for device positioning and deployment. The mitral valve prosthesis was implanted with mild mitral regurgitation. The postoperative course was uneventful and at 30-day follow-up the patient is in NYHA Class I, with good function of the mitral valve bioprosthesis. This procedure shows that percutaneous transfemoral transcatheter mitral valve implantation is feasible, safe and successful. Further experience is needed to render this procedure clinically available.

Effect of the mitral valve on diastolic flow patterns

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, Jung Hee; Vedula, Vijay; Mittal, Rajat, E-mail: mittal@jhu.edu

2014-12-15

The leaflets of the mitral valve interact with the mitral jet and significantly impact diastolic flow patterns, but the effect of mitral valve morphology and kinematics on diastolic flow and its implications for left ventricular function have not been clearly delineated. In the present study, we employ computational hemodynamic simulations to understand the effect of mitral valve leaflets on diastolic flow. A computational model of the left ventricle is constructed based on a high-resolution contrast computed-tomography scan, and a physiological inspired model of the mitral valve leaflets is synthesized from morphological and echocardiographic data. Simulations are performed with a diodemore » type valve model as well as the physiological mitral valve model in order to delineate the effect of mitral-valve leaflets on the intraventricular flow. The study suggests that a normal physiological mitral valve promotes the formation of a circulatory (or “looped”) flow pattern in the ventricle. The mitral valve leaflets also increase the strength of the apical flow, thereby enhancing apical washout and mixing of ventricular blood. The implications of these findings on ventricular function as well as ventricular flow models are discussed.« less

Assessment of mitral regurgitation in dogs: comparison of results of echocardiography with magnetic resonance imaging.

PubMed

Sargent, J; Connolly, D J; Watts, V; Mõtsküla, P; Volk, H A; Lamb, C R; Fuentes, V Luis

2015-11-01

Echocardiography is used routinely to assess mitral regurgitation severity, but echocardiographic measures of mitral regurgitation in dogs have not been compared with other quantitative methods. The study aim was to compare echocardiographic measures of mitral regurgitation with cardiac magnetic resonance imaging-derived mitral regurgitant fraction in small-breed dogs. Dogs with myxomatous mitral valve disease scheduled for magnetic resonance imaging assessment of neurological disease were recruited. Correlations were tested between cardiac magnetic resonance imaging-derived mitral regurgitant fraction and the following echocardiographic measures: vena contracta/aortic diameter, transmitral E-wave velocity, amplitude of mitral prolapse/aortic diameter, diastolic left ventricular diameter:aortic diameter, left atrium:aortic diameter, mitral regurgitation jet area ratio and regurgitant fraction calculated using the proximal isovelocity surface area method. Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction was attempted in 21 dogs. Twelve consecutive, complete studies were obtained and 10 dogs were included in the final analysis: vena contracta/aortic diameter (r = 0 · 89, p = 0 · 001) and E-wave velocity (r = 0 · 86, p = 0 · 001) had the strongest correlations with cardiac magnetic resonance imaging-derived mitral regurgitant fraction. E velocity had superior repeatability and could be measured in all dogs. The presence of multiple jets precluded vena contracta/aortic diameter measurement in one dog. Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction is feasible but technically demanding. The echocardiographic measures that correlated most closely with cardiac magnetic resonance imaging-derived mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity. © 2015 British Small Animal Veterinary Association.

Association Of Tricuspid Regurgitation And Severity Of Mitral Stenosis In Patients With Rheumatic Heart Disease.

PubMed

Ahmed, Rehan; Kazmi, Nasir; Naz, Farhat; Malik, Saqib; Gillani, Saima

2016-01-01

Rheumatic heart disease is a common ailment in Pakistan and Mitral stenosis is its flag bearer Severity of mitral stenosis is the key factor in deciding for mitral valve surgery. This case series study was conducted at Ayub Teaching Hospital .Cases of Rheumatic heart disease with mitral stenosis were diagnosed clinically. 2D echocardiography was used to find severity of mitral stenosis. Data was entered into SPSS-17.0 and results were recorded and analysed. Pearson's two tailed correlation was used to find the correlation between presence of tricuspid regurgitation in patients with severe mitral stenosis, p was <0.05. A total 35 patients with pure mitral stenosis were included in study, out of which 8 were male and 27 were females. Mean age in males was 34.5±15.85 years while in females it was 31±8 years. Twenty-two out of 35 (62.86%) patients had tricuspid regurgitation while 13 out 35 (37.14%) had no tricuspid regurgitation. Mean (MVA) mitral valve area in patients with tricuspid regurgitation was 0.84±0.3 cm2 while mean (MVA) mitral valve area in patients without tricuspid regurgitation was 1.83±0.7 cm2. Mean left atrial (L.A) size was 45.23±1.5 mm2 in patients with tricuspid regurgitation, while it was 44.13±6.14 mm2 in patients without tricuspid regurgitation. Mean RSVP was 57.5mmHg in patients with tricuspid regurgitation while RSVP could not be calculated in patients without tricuspid regurgitation. It was concluded that tricuspid regurgitation was strongly associated with severe mitral stenosis as almost all patients with severe mitral stenosis had tricuspid regurgitation and none of the patients with mild mitral stenosis had tricuspid regurgitation.

Mechanisms of valve competency after mitral valve annuloplasty for ischaemic mitral regurgitation using the Geoform ring: insights from three-dimensional echocardiography.

PubMed

Armen, Todd A; Vandse, Rashmi; Crestanello, Juan A; Raman, Subha V; Bickle, Katherine M; Nathan, Nadia S

2009-01-01

Left ventricular remodelling leads to functional mitral regurgitation resulting from annular dilatation, leaflet tethering, tenting, and decreased leaflet coaptation. Mitral valve annuloplasty restores valve competency, improving the patient's functional status and ventricular function. This study was designed to evaluate the mechanisms underlying mitral valve competency after the implantation of a Geoform annuloplasty ring using three-dimensional (3D) echocardiography. Seven patients (mean age of 65 years) with ischaemic mitral regurgitation underwent mitral valve annuloplasty with the Geoform ring and coronary artery bypass surgery. Pre- and post-operative 3D echocardiograms were performed. Following mitral annuloplasty, mitral regurgitation decreased from 3.4+/-0.2 to 0.9+/-0.3 (P-value<0.0001), mitral valve tenting volume from 13+/-1.7 to 3.2+/-0.3 mL (P-value<0.001), annulus area from 12.6+/-1.0 to 3.3+/-0.2 cm2 (P-value<0.0001), valve circumference from 13+/-0.5 to 7.3+/-0.3 cm (P-value<0.0001), septolateral distance from 2.1+/-0.1 to 1.4+/-0.06 cm (P-value<0.01) and intercommissural distance from 3.4+/-0.1 to 2.7+/-0.03 cm (P-value<0.03). There was significant decrease in the septolateral distance at the level of A2-P2 with respect to other regions. These geometric changes were associated with the improvement in the NYHA class from 3.1+/-0.3 to 1.3+/-0.3 (P-value<0.002). The mitral valve annuloplasty with the Geoform ring restores leaflet coaptation and eliminates mitral regurgitation by effectively modifying the mitral annular geometry.

Postsynaptic elevation of calcium induces persistent depression of developing neuromuscular synapses.

PubMed

Cash, S; Dan, Y; Poo, M M; Zucker, R

1996-04-01

Synaptic activity is known to modulate neuronal connectivity in the nervous system. At developing Xenopus neuromuscular synapses in culture, repetitive postsynaptic application of ACh near the synapse leads to immediate and persistent synaptic depression, which was shown to be caused by reduction of presynaptic evoked transmitter release. However, little depression was found when ACh was applied to the muscle 20 microns or further from the synapse. Fluorescence imaging of cytosolic Ca2+ ([Ca2+]i) showed that each ACh pulse induced a transient elevation of myocyte [Ca2+]i that spread approximately 20 microns. Local photoactivated release of Ca2+ from the caged Ca2+ chelators nitr-5 or nitrophen in the postsynaptic cell was sufficient to induce persistent synaptic depression. These results support a model in which localized Ca2+ influx into the postsynaptic myocyte initiates transsynaptic retrograde modulation of presynaptic secretion mechanisms.

The role of microglia in synaptic stripping and synaptic degeneration: a revised perspective

PubMed Central

Hugh Perry, V; O'Connor, Vincent

2010-01-01

Chronic neurodegenerative diseases of the CNS (central nervous system) are characterized by the loss of neurons. There is, however, growing evidence to show that an early stage of this process involves degeneration of presynaptic terminals prior to the loss of the cell body. Synaptic plasticity in CNS pathology has been associated with microglia and the phenomenon of synaptic stripping. We review here the evidence for the involvement of microglia in synaptic stripping and synapse degeneration and we conclude that this is a case of guilt by association. In disease models of chronic neurodegeneration, there is no evidence that microglia play an active role in either synaptic stripping or synapse degeneration, but the degeneration of the synapse and the envelopment of a degenerating terminal appears to be a neuron autonomous event. We highlight here some of the gaps in our understanding of synapse degeneration in chronic neurodegenerative disease. PMID:20967131

Somato-dendritic synapses in the nucleus reticularis thalami of the rat.

PubMed

Csillik, B; Pálfi, A; Gulya, K; Mihály, A; Knyihár-Csillik, Elizabeth

2002-01-01

In the reticular nucleus of the rat thalamus, about 30% of the synapses are brought about by the perikarya of parvalbumin-immunopositive neurons, which establish somato-dendritic synapses with large dendrites of nerve cells of specific thalamic nuclei. Although the parvalbumin-immunopositive presynaptic structures bear resemblance to goblet-like or calyciform axonal endings, electron microscopic immunocytochemistry and in situ hybridization revealed that these structures are parts of the perikaryal cytoplasm studded with synaptic vesicles. In about 15% of the somato-dendritic synapses, axons are seen to be in synaptic contact with the parvalbumin-immunoreactive perikaryon. Double immunohistochemical staining revealed that the parvalbumin immunoreactive presynaptic perikarya and dendrites contained GABA. It is assumed that the peculiar somato-dendritic synaptic complexes subserve the goal of filtration of impulses arriving at the reticular nucleus from various thalamic nuclei, thus processing them for further sampling.

Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

PubMed

Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B; Hubbard, Dusten D; Hanka, Dakota C; Gonzalez, Paola V; Kuwajima, Masaaki; Mendenhall, John M; Parker, Patrick H; Abraham, Wickliffe C; Sejnowski, Terrence J; Harris, Kristen M

2018-03-06

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

Metaplasticity of hypothalamic synapses following in vivo challenge.

PubMed

Kuzmiski, J Brent; Pittman, Quentin J; Bains, Jaideep S

2009-06-25

Neural networks that regulate an organism's internal environment must sense perturbations, respond appropriately, and then reset. These adaptations should be reflected as changes in the efficacy of the synapses that drive the final output of these homeostatic networks. Here we show that hemorrhage, an in vivo challenge to fluid homeostasis, induces LTD at glutamate synapses onto hypothalamic magnocellular neurosecretory cells (MNCs). LTD requires the activation of postsynaptic alpha2-adrenoceptors and the production of endocannabinoids that act in a retrograde fashion to inhibit glutamate release. In addition, both hemorrhage and noradrenaline downregulate presynaptic group III mGluRs. This loss of mGluR function allows high-frequency activity to potentiate these synapses from their depressed state. These findings demonstrate that noradrenaline controls a form of metaplasticity that may underlie the resetting of homeostatic networks following a successful response to an acute physiological challenge.

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus

PubMed Central

Heise, Christopher; Schroeder, Jan C.; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R.; Schmeisser, Michael J.; Boeckers, Tobias M.

2016-01-01

Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies. PMID:27199660

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus.

PubMed

Heise, Christopher; Schroeder, Jan C; Schoen, Michael; Halbedl, Sonja; Reim, Dominik; Woelfle, Sarah; Kreutz, Michael R; Schmeisser, Michael J; Boeckers, Tobias M

2016-01-01

Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies.

Somatic and neuritic spines on tyrosine hydroxylase–immunopositive cells of rat retina

PubMed Central

Fasoli, Anna; Dang, James; Johnson, Jeffrey S.; Gouw, Aaron H.; Iseppe, Alex Fogli; Ishida, Andrew T.

2018-01-01

Dopamine- and tyrosine hydroxylase–immunopositive cells (TH cells) modulate visually driven signals as they flow through retinal photoreceptor, bipolar, and ganglion cells. Previous studies suggested that TH cells release dopamine from varicose axons arborizing in the inner and outer plexiform layers after glutamatergic synapses depolarize TH cell dendrites in the inner plexiform layer and these depolarizations propagate to the varicosities. Although it has been proposed that these excitatory synapses are formed onto appendages resembling dendritic spines, spines have not been found on TH cells of most species examined to date or on TH cell somata that release dopamine when exposed to glutamate receptor agonists. By use of protocols that preserve proximal retinal neuron morphology, we have examined the shape, distribution, and synapse-related immunoreactivity of adult rat TH cells. We report here that TH cell somata, tapering and varicose inner plexiform layer neurites, and varicose outer plexiform layer neurites all bear spines, that some of these spines are immunopositive for glutamate receptor and postsynaptic density proteins (viz., GluR1, GluR4, NR1, PSD-95, and PSD-93), that TH cell somata and tapering neurites are also immunopositive for a γ-aminobutyric acid (GABA) receptor subunit (GABAARα1), and that a synaptic ribbon-specific protein (RIBEYE) is found adjacent to some colocalizations of GluR1 and TH in the inner plexiform layer. These results identify previously undescribed sites at which glutamatergic and GABAergic inputs may stimulate and inhibit dopamine release, especially at somata and along varicose neurites that emerge from these somata and arborize in various levels of the retina. PMID:28035673

When the gold standard is not always golden: The value of invasive hemodynamic assessment to overcome the pitfalls of echocardiography in challenging cases of mitral stenosis.

PubMed

Harper, Yenal; Salem, Salem A; Alsafwah, Shadwan; Koshy, Santhosh; Garg, Nadish

2018-01-01

Mitral stenosis is a uncommon valvular lesion in the developed countries. Noninvasive evaluation is the first-line modality for assessment of mitral stenosis, however the noninvasive methods may have limitations in certain cases. Invasive hemodynamics can be used as adjunct tool for assessment of mitral stenosis in such difficult cases. Mitral valve using three-dimensional planimetry is a promising technique for assessment of mitral stenosis. © 2018 Wiley Periodicals, Inc.

Role of echocardiography/Doppler in cardiogenic shock: silent mitral regurgitation.

PubMed

Goldman, A P; Glover, M U; Mick, W; Pupello, D F; Hiro, S P; Lopez-Cuenca, E; Maniscalco, B S

1991-08-01

Two cases of cardiogenic shock and pulmonary edema due to acute, severe, silent mitral regurgitation are discussed. The mechanism for the mitral regurgitation was papillary muscle rupture in the setting of acute myocardial infarction. Echocardiography established the presence, severity, and cause of the mitral regurgitation and the associated hyperdynamic left ventricular function in the setting of cardiogenic shock. Transesophageal echocardiography is excellent for assessing the mitral valve in critically ill patients in whom transthoracic echocardiography may be inadequate or misleading. This allowed for emergency mitral valve replacement without prolonged attempts at medical stabilization.

Perineuronal Net Protein Neurocan Inhibits NCAM/EphA3 Repellent Signaling in GABAergic Interneurons.

PubMed

Sullivan, Chelsea S; Gotthard, Ingo; Wyatt, Elliott V; Bongu, Srihita; Mohan, Vishwa; Weinberg, Richard J; Maness, Patricia F

2018-04-18

Perineuronal nets (PNNs) are implicated in closure of critical periods of synaptic plasticity in the brain, but the molecular mechanisms by which PNNs regulate synapse development are obscure. A receptor complex of NCAM and EphA3 mediates postnatal remodeling of inhibitory perisomatic synapses of GABAergic interneurons onto pyramidal cells in the mouse frontal cortex necessary for excitatory/inhibitory balance. Here it is shown that enzymatic removal of PNN glycosaminoglycan chains decreased the density of GABAergic perisomatic synapses in mouse organotypic cortical slice cultures. Neurocan, a key component of PNNs, was expressed in postnatal frontal cortex in apposition to perisomatic synapses of parvalbumin-positive interneurons. Polysialylated NCAM (PSA-NCAM), which is required for ephrin-dependent synapse remodeling, bound less efficiently to neurocan than mature, non-PSA-NCAM. Neurocan bound the non-polysialylated form of NCAM at the EphA3 binding site within the immunoglobulin-2 domain. Neurocan inhibited NCAM/EphA3 association, membrane clustering of NCAM/EphA3 in cortical interneuron axons, EphA3 kinase activation, and ephrin-A5-induced growth cone collapse. These studies delineate a novel mechanism wherein neurocan inhibits NCAM/EphA3 signaling and axonal repulsion, which may terminate postnatal remodeling of interneuron axons to stabilize perisomatic synapses in vivo.

The Coupling between Ca2+ Channels and the Exocytotic Ca2+ Sensor at Hair Cell Ribbon Synapses Varies Tonotopically along the Mature Cochlea

PubMed Central

Cho, Soyoun

2017-01-01

The cochlea processes auditory signals over a wide range of frequencies and intensities. However, the transfer characteristics at hair cell ribbon synapses are still poorly understood at different frequency locations along the cochlea. Using recordings from mature gerbils, we report here a surprisingly strong block of exocytosis by the slow Ca2+ buffer EGTA (10 mM) in basal hair cells tuned to high frequencies (∼30 kHz). In addition, using recordings from gerbil, mouse, and bullfrog auditory organs, we find that the spatial coupling between Ca2+ influx and exocytosis changes from nanodomain in low-frequency tuned hair cells (∼<2 kHz) to progressively more microdomain in high-frequency cells (∼>2 kHz). Hair cell synapses have thus developed remarkable frequency-dependent tuning of exocytosis: accurate low-latency encoding of onset and offset of sound intensity in the cochlea's base and submillisecond encoding of membrane receptor potential fluctuations in the apex for precise phase-locking to sound signals. We also found that synaptic vesicle pool recovery from depletion was sensitive to high concentrations of EGTA, suggesting that intracellular Ca2+ buffers play an important role in vesicle recruitment in both low- and high-frequency hair cells. In conclusion, our results indicate that microdomain coupling is important for exocytosis in high-frequency hair cells, suggesting a novel hypothesis for why these cells are more susceptible to sound-induced damage than low-frequency cells; high-frequency inner hair cells must have a low Ca2+ buffer capacity to sustain exocytosis, thus making them more prone to Ca2+-induced cytotoxicity. SIGNIFICANCE STATEMENT In the inner ear, sensory hair cells signal reception of sound. They do this by converting the sound-induced movement of their hair bundles present at the top of these cells, into an electrical current. This current depolarizes the hair cell and triggers the calcium-induced release of the neurotransmitter glutamate that activates the postsynaptic auditory fibers. The speed and precision of this process enables the brain to perceive the vital components of sound, such as frequency and intensity. We show that the coupling strength between calcium channels and the exocytosis calcium sensor at inner hair cell synapses changes along the mammalian cochlea such that the timing and/or intensity of sound is encoded with high precision. PMID:28154149

Somato-synaptic variation of GABA(A) receptors in cultured murine cerebellar granule cells: investigation of the role of the alpha6 subunit.

PubMed

Mellor, J R; Wisden, W; Randall, A D

2000-07-10

Electrophysiological investigation of cultured cerebellar murine granule cells revealed differences between the GABA(A) receptors at inhibitory synapses and those on the cell body. Specifically, mIPSCs decayed more rapidly than cell body receptors deactivated, the mean single channel conductance at the synapse (32 pS) was greater than that at cell body (21 pS) and only cell body receptors were sensitive to Zn(2+) (150 microM), which depressed response amplitude by 82+/-5% and almost doubled the rate of channel deactivation. The GABA(A) receptor alpha6 subunit is selectively expressed in cerebellar granule cells. Although concentrated at synapses, it is also found on extrasynaptic membranes. Using a mouse line (Deltaalpha6lacZ) lacking this subunit, we investigated its role in the somato-synaptic differences in GABA(A) receptor function. All differences between cell body and synaptic GABA(A) receptors observed in wild-type (WT) granule cells persisted in Deltaalpha6lacZ cells, thus demonstrating that they are not specifically due to the cellular distribution of the alpha6 subunit. However, mIPSCs from WT and Deltaalpha6lacZ cells differed in both their kinetics (faster decay in WT cells) and underlying single channel conductance (32 pS WT, 25 pS Deltaalpha6lacZ). This provides good evidence for a functional contribution of the alpha6 subunit to postsynaptic GABA(A) receptors in these cells. Despite this, deactivation kinetics of mIPSCs in WT and Deltaalpha6lacZ granule cells exhibited similar benzodiazepene (BDZ) sensitivity. This suggests that the enhanced BDZ-induced ataxia seen in Deltaalpha6lacZ mice may reflect physiological activity at extrasynaptic receptors which, unlike those at synapses, display differential BDZ-sensitivity in WT and Deltaalpha6lacZ granule cells (Jones, A.M., Korpi, E.R., McKernan, R.M., Nusser, Z., Pelz, R., Makela, R., Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J.H., Wisden, W., 1997. Ligand-gated ion channel partnerships: GABA(A) receptor alpha(6) subunit inactivation inhibits delta subunit expression. Journal of Neuroscience 17, 1350-1362).

The impact of concomitant pulmonary hypertension on early and late outcomes following surgery for mitral stenosis.

PubMed

Yang, Bo; DeBenedictus, Christina; Watt, Tessa; Farley, Sean; Salita, Alona; Hornsby, Whitney; Wu, Xiaoting; Herbert, Morley; Likosky, Donald; Bolling, Steven F

2016-08-01

To provide initial evidence on the management of mitral stenosis and pulmonary hypertension (PH) based on short-term and long-term outcomes following mitral valve surgery. Consecutive patients with mitral stenosis (n = 317) who had undergone mitral valve surgery between 1992 and 2014 with recorded pulmonary artery pressure (PAP) data were reviewed. PH severity, based on systolic PAP, was categorized as mild (35 to 44 mm Hg), moderate (45 to 59 mm Hg), or severe (>60 mm Hg). Primary outcomes were 30-day mortality and long-term survival. There were no significant between-group differences in age or preoperative comorbidities. Mitral valve surgery included mitral valve replacement (78%) and repair (22%). The severe PH group had more mitral valve replacement (81%; P = .04), severe tricuspid valve regurgitation (31%; P = .003), right heart failure (17%; P = .02), and concomitant tricuspid valve procedures (46%; P < .001). For severe PH, 30-day mortality was 9%, with no significant group differences. Ten- and 12-year survival were significantly worse in the moderate-severe PH group (58% and 51%, respectively) compared with the normal PAP-mild PH group (83% and 79%, respectively) with a hazard ratio of 2.98 (95% confidence interval, 1.55-5.75; P = .001). Ten-year survival after mitral valve surgery for mitral stenosis was inversely associated with preoperative PAP. Mitral valve surgery can be performed with acceptable 30-day mortality for patients with mitral stenosis and moderate to severe PH, but long-term survival is impaired by moderate to severe PH. Patients with mitral stenosis and mild PH (systolic PAP 35-44 mm Hg) should be considered for mitral valve surgery. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

An Investigation of Tenascin-C Levels in Rheumatic Mitral Stenosis and Their Response to Percutaneous Mitral Balloon Valvuloplasty

PubMed Central

Celik, Ahmet; Gunebakmaz, Ozgur; Baran, Oguzhan; Dogdu, Orhan; Elcik, Deniz; Kobat, Mehmet Ali; Balin, Mehmet; Erdem, Kenan; Aydin, Suleyman; Ozdogru, Ibrahim; Topsakal, Ramazan

2012-01-01

Objective The purpose of this study was to evaluate the tenascin-C levels in severe rheumatic mitral stenosis before and after percutaneous mitral balloon valvuloplasty (PMBV). Subjects and Methods Forty patients with severe mitral stenosis requiring PMBV and 20 age-matched healthy subjects were included in the study. The mitral valve areas, mitral gradients and systolic pulmonary artery pressure (sPAP) were measured by echocardiography. The sPAP values and mitral gradients were also measured by catheterization before and after PMBV. The blood tenascin-C levels were measured before PMBV and 1 month after the procedure. Results The echocardiographic mean mitral gradients had a significant decrease after PMBV (11.7 ± 2.8 vs. 5.6 ± 1.7 mm Hg; p < 0.001) and also those of catheterization (13.9 ± 4.4 vs. 4.0 ± 2.4 mm Hg; p < 0.001). Mitral valve areas increased significantly after PMBV (from 1.1 ± 0.1 to 1.8 ± 0.2 cm2, p < 0.001). Tenascin-C levels decreased significantly in patients after PMBV (from 15.0 ± 3.8 to 10.9 ± 3.1 ng/ml; p < 0.001). Tenascin-C levels were higher in patients with mitral stenosis before PMBV than in healthy subjects (15.0 ± 3.8 and 9.4 ± 2.9 ng/ml; p < 0.001, respectively). There were no significant differences between patients with mitral stenosis after PMBV and healthy subjects (10.9 ± 3.1 and 9.4 ± 2.9 ng/ml; p = 0.09, respectively). There was a significant positive correlation between tenascin-C levels and sPAP (r = 0.508, p < 0.001). In multivariant analysis, tenascin-C predicted mitral stenosis (p = 0.004, OR: 2.31). Conclusions Tenascin-C was an independent predictor for rheumatic mitral stenosis. PMID:22889719

Sparse Coding and Lateral Inhibition Arising from Balanced and Unbalanced Dendrodendritic Excitation and Inhibition

PubMed Central

Migliore, Michele; Hines, Michael L.; Shepherd, Gordon M.

2014-01-01

The precise mechanism by which synaptic excitation and inhibition interact with each other in odor coding through the unique dendrodendritic synaptic microcircuits present in olfactory bulb is unknown. Here a scaled-up model of the mitral–granule cell network in the rodent olfactory bulb is used to analyze dendrodendritic processing of experimentally determined odor patterns. We found that the interaction between excitation and inhibition is responsible for two fundamental computational mechanisms: (1) a balanced excitation/inhibition in strongly activated mitral cells, leading to a sparse representation of odorant input, and (2) an unbalanced excitation/inhibition (inhibition dominated) in surrounding weakly activated mitral cells, leading to lateral inhibition. These results suggest how both mechanisms can carry information about the input patterns, with optimal level of synaptic excitation and inhibition producing the highest level of sparseness and decorrelation in the network response. The results suggest how the learning process, through the emergent development of these mechanisms, can enhance odor representation of olfactory bulb. PMID:25297097

Paired-Pulse Depression at Photoreceptor Synapses

PubMed Central

Rabl, Katalin; Cadetti, Lucia; Thoreson, Wallace B.

2011-01-01

Synaptic depression produced by repetitive stimulation is likely to be particularly important in shaping responses of second-order retinal neurons at the tonically active photoreceptor synapse. We analyzed the time course and mechanisms of synaptic depression at rod and cone synapses using paired-pulse protocols involving two complementary measurements of exocytosis: (1) paired whole-cell recordings of the postsynaptic current (PSC) in second-order retinal neurons and (2) capacitance measurements of vesicular membrane fusion in rods and cones. PSCs in ON bipolar, OFF bipolar, and horizontal cells evoked by stimulation of either rods or cones recovered from paired-pulse depression (PPD) at rates similar to the recovery of exocytotic capacitance changes in rods and cones. Correlation between presynaptic and postsynaptic measures of recovery from PPD suggests that 80 –90% of the depression at these synapses is presynaptic in origin. Consistent with a predominantly presynaptic mechanism, inhibiting desensitization of postsynaptic glutamate receptors had little effect on PPD. The depression of exocytotic capacitance changes exceeded depression of the presynaptic calcium current, suggesting that it is primarily caused by a depletion of synaptic vesicles. In support of this idea, limiting Ca2+ influx by using weaker depolarizing stimuli promoted faster recovery from PPD. Although cones exhibit much faster exocytotic kinetics than rods, exocytotic capacitance changes recovered from PPD at similar rates in both cell types. Thus, depression of release is not likely to contribute to differences in the kinetics of transmission from rods and cones. PMID:16510733

Transactivation of TrkB by Sigma-1 receptor mediates cocaine-induced changes in dendritic spine density and morphology in hippocampal and cortical neurons

PubMed Central

Ka, Minhan; Kook, Yeon-Hee; Liao, Ke; Buch, Shilpa; Kim, Woo-Yang

2016-01-01

Cocaine is a highly addictive narcotic associated with dendritic spine plasticity in the striatum. However, it remains elusive whether cocaine modifies spines in a cell type-specific or region-specific manner or whether it alters different types of synapses in the brain. In addition, there is a paucity of data on the regulatory mechanism(s) involved in cocaine-induced modification of spine density. In the current study, we report that cocaine exposure differentially alters spine density, spine morphology, and the types of synapses in hippocampal and cortical neurons. Cocaine exposure in the hippocampus resulted in increased spine density, but had no significant effect on cortical neurons. Although cocaine exposure altered spine morphology in both cell types, the patterns of spine morphology were distinct for each cell type. Furthermore, we observed that cocaine selectively affects the density of excitatory synapses. Intriguingly, in hippocampal neurons cocaine-mediated effects on spine density and morphology involved sigma-1 receptor (Sig-1 R) and its downstream TrkB signaling, which were not the case in cortical neurons. Furthermore, pharmacological inhibition of Sig-1 R prevented cocaine-induced TrkB activation in hippocampal neurons. Our findings reveal a novel mechanism by which cocaine induces selective changes in spine morphology, spine density, and synapse formation, and could provide insights into the cellular basis for the cognitive impairment observed in cocaine addicts. PMID:27735948

When what appears to be mitral stenosis is not: diagnostic and therapeutic implications.

PubMed

Almeida, Inês; Caetano, Francisca; Trigo, Joana; Mota, Paula; Cachulo, Maria do Carmo; Antunes, Manuel; Leitão Marques, António

2014-01-01

The authors report the case of a 53-year-old man, with a long-standing history of mild mitral stenosis, admitted for worsening fatigue. Transthoracic echocardiography (limited by poor image quality) showed mitral annular calcification, leaflets that were difficult to visualize and an estimated mitral valve area of 1.8 cm(2) by the pressure half-time method. However, elevated mean transmitral and right ventricle/right atrium gradients were identified (39 and 117 mmHg, respectively). This puzzling discrepancy in the echocardiographic findings prompted investigation by transesophageal echocardiography, which revealed an echogenic structure adjacent to the mitral annulus, causing severe obstruction (effective orifice area 0.7 cm(2)). The suspicion of supravalvular mitral ring was confirmed during surgery. Following ring resection and mitral valve replacement there was significant improvement in the patient's clinical condition and normalization of the left atrium/left ventricle gradient. Supravalvular mitral ring is an unusual cause of congenital mitral stenosis, characterized by an abnormal ridge of connective tissue on the atrial side of the mitral valve, which often obstructs mitral valve inflow. Few cases have been reported, most of them in children with concomitant congenital abnormalities. Diagnosis of a supravalvular mitral ring is challenging, since it is very difficult to visualize in most diagnostic tests. It was the combination of clinical and various echocardiographic findings that led us to suspect this very rare condition, enabling appropriate treatment, with excellent long-term results. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

Fibroblast Growth Factor 22 Contributes to the Development of Retinal Nerve Terminals in the Dorsal Lateral Geniculate Nucleus

PubMed Central

Singh, Rishabh; Su, Jianmin; Brooks, Justin; Terauchi, Akiko; Umemori, Hisashi; Fox, Michael A.

2012-01-01

At least three forms of signaling between pre- and postsynaptic partners are necessary during synapse formation. First, “targeting” signals instruct presynaptic axons to recognize and adhere to the correct portion of a postsynaptic target cell. Second, trans-synaptic “organizing” signals induce differentiation in their synaptic partner so that each side of the synapse is specialized for synaptic transmission. Finally, in many regions of the nervous system an excess of synapses are initially formed, therefore “refinement” signals must either stabilize or destabilize the synapse to reinforce or eliminate connections, respectively. Because of both their importance in processing visual information and their accessibility, retinogeniculate synapses have served as a model for studying synaptic development. Molecular signals that drive retinogeniculate “targeting” and “refinement” have been identified, however, little is known about what “organizing” cues are necessary for the differentiation of retinal axons into presynaptic terminals. To identify such “organizing” cues, we used microarray analysis to assess whether any target-derived “synaptic organizers” were enriched in the mouse dorsal lateral geniculate nucleus (dLGN) during retinogeniculate synapse formation. One candidate “organizing” molecule enriched in perinatal dLGN was FGF22, a secreted cue that induces the formation of excitatory nerve terminals in muscle, hippocampus, and cerebellum. In FGF22 knockout mice, the development of retinal terminals in dLGN was impaired. Thus, FGF22 is an important “organizing” cue for the timely development of retinogeniculate synapses. PMID:22363257

Auditory hair cell innervational patterns in lizards.

PubMed

Miller, M R; Beck, J

1988-05-22

The pattern of afferent and efferent innervation of two to four unidirectional (UHC) and two to nine bidirectional (BHC) hair cells of five different types of lizard auditory papillae was determined by reconstruction of serial TEM sections. The species studies were Crotaphytus wislizeni (iguanid), Podarcis (Lacerta) sicula and P. muralis (lacertids), Ameiva ameiva (teiid), Coleonyx variegatus (gekkonid), and Mabuya multifasciata (scincid). The main object was to determine in which species and in which hair cell types the nerve fibers were innervating only one (exclusive innervation), or two or more hair cells (nonexclusive innervation); how many nerve fibers were supplying each hair cell; how many synapses were made by the innervating fibers; and the total number of synapses on each hair cell. In the species studies, efferent innervation was limited to the UHC, and except for the iguanid, C. wislizeni, it was nonexclusive, each fiber supplying two or more hair cells. Afferent innervation varied both with the species and the hair cell types. In Crotaphytus, both the UHC and the BHC were exclusively innervated. In Podarcis and Ameiva, the UHC were innervated exclusively by some fibers but nonexclusively by others (mixed pattern). In Coleonyx, the UHC were exclusively innervated but the BHC were nonexclusively innervated. In Mabuya, both the UHC and BHC were nonexclusively innervated. The number of afferent nerve fibers and the number of afferent synapses were always larger in the UHC than in the BHC. In Ameiva, Podarcis, and Mabuya, groups of bidirectionally oriented hair cells occur in regions of cytologically distinct UHC, and in Ameiva, unidirectionally oriented hair cells occur in cytologically distinct BHC regions.

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

PubMed

Kuramitsu, S; Ohno, M; Ohka, F; Shiina, S; Yamamichi, A; Kato, A; Tanahashi, K; Motomura, K; Kondo, G; Kurimoto, M; Senga, T; Wakabayashi, T; Natsume, A

2015-10-01

The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

Transcatheter Mitral Valve Replacement for Native and Failed Bioprosthetic Mitral Valves

PubMed Central

Sarkar, Kunal; Reardon, Michael J.; Little, Stephen H.; Barker, Colin M.; Kleiman, Neal S.

2017-01-01

Transcatheter mitral valve replacement (TMVR) is a novel approach for treatment of severe mitral regurgitation. A number of TMVR devices are currently undergoing feasibility trials using both transseptal and transapical routes for device delivery. Overall experience worldwide is limited to fewer than 200 cases. At present, the 30-day mortality exceeds 30% and is attributable to both patient- and device-related factors. TMVR has been successfully used to treat patients with degenerative mitral stenosis (DMS) as well as failed mitral bioprosthesis and mitral repair using transcatheter mitral valve-in-valve (TMViV)/valve-in-ring (ViR) repair. These patients are currently treated with devices designed for transcatheter aortic valve replacement. Multicenter registries have been initiated to collect outcomes data on patients currently undergoing TMViV/ViR and TMVR for DMS and have confirmed the feasibility of TMVR in these patients. However, the high periprocedural and 30-day event rates underscore the need for further improvements in device design and multicenter randomized studies to delineate the role of these technologies in patients with mitral valve disease. PMID:29743999

Cellular localization of the atypical isoforms of protein kinase C (aPKCζ/PKMζ and aPKCλ/ι) on the neuromuscular synapse.

PubMed

Besalduch, Núria; Lanuza, Maria A; Garcia, Neus; Obis, Teresa; Santafe, Manel M; Tomàs, Marta; Priego, Mercedes; Tomàs, Josep

2013-11-27

Several classic and novel protein kinase C (PKC) isoforms are selectively distributed in specific cell types of the adult neuromuscular junction (NMJ), in the neuron, glia and muscle components, and are involved in many functions, including neurotransmission. Here, we investigate the presence in this paradigmatic synapse of atypical PKCs, full-length atypical PKC zeta (aPKCζ), its separated catalytic part (PKMζ) and atypical lambda-iota PKC (aPKCλ/ι). High resolution immunohistochemistry was performed using a pan-atypical PKC antibody. Our results show moderate immunolabeling on the three cells (presynaptic motor nerve terminal, teloglial Schwann cell and postsynaptic muscle cell) suggesting the complex involvement of atypical PKCs in synaptic function. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

AMPA receptor activation controls type I metabotropic glutamate receptor signalling via a tyrosine kinase at parallel fibre-Purkinje cell synapses.

PubMed

Auger, Céline; Ogden, David

2010-08-15

Metabotropic glutamate receptors type 1 (mGluR1s) and ionotropic AMPA receptors (AMPARs) are colocalized at parallel fibre (PF) to Purkinje cell synapses of the cerebellum. Single stimulation of PFs activates fast AMPAR excitatory postsynaptic currents, whereas the activation of mGluR1s requires burst stimulation. mGluR1s signal through several pathways in Purkinje cells and the most prominent is the activation of a slow EPSC (sEPSC). To separate the two synaptic currents, studies of the sEPSC have commonly been performed in the presence of AMPA/KA receptor antagonists. We show here in rat cerebellar slices that inhibition of the fast EPSC by AMPAR antagonists strongly and selectively potentiates the mGluR1 sEPSC, showing a negative regulation of mGluR1 by AMPAR. This effect is observed with low concentrations of NBQX (300 nM to 1 microM), with the selective AMPAR antagonist GYKI 53655 and also with gamma-DGG, a low affinity glutamate receptor antagonist. When photorelease of glutamate from MNI-glutamate was used to study the postsynaptic responses in isolation, AMPAR inhibition produced a similar potentiation of the mGluR1 sEPSC, showing that the interaction is postsynaptic. Finally, perfusion of the postsynaptic cell with PP1, an inhibitor of src-family tyrosine kinase, increased the amplitude of the mGluR1 sEPSC and occluded the effect of AMPAR inhibition. Thus, at PF to Purkinje cell synapses, AMPAR activation inhibits the mGluR1 sEPSC via activation of a src-family tyrosine kinase. Consequently mGluR1 signalling will be more sensitive to spillover of glutamate than to local synaptic release. Furthermore, it will be enhanced at silent PF synapses which are the majority in Purkinje cells.

Mitral valve stenosis caused by abnormal pannus extension over the prosthetic ring and leaflets after Duran ring mitral annuloplasty.

PubMed

Yunoki, Junji; Minato, Naoki; Katayama, Yuji; Sato, Hisashi

2009-01-01

We treated a 61-year-old woman with mitral stenosis caused by pannus formation after Duran ring annuloplasty. Pannus overgrowth on the ring with extension onto both leaflets narrowed the mitral orifice and severely restricted the mobility of the valve leaflets. Mitral valve replacement with a St. Jude Medical mechanical heart valve prosthesis was successfully performed, and the postoperative course was uneventful. Patients undergoing Duran ring annuloplasty should be followed up with the consideration of possible mitral stenosis caused by pannus extension, as the cause for pannus formation remains unclear.

Intraoperative application of geometric three-dimensional mitral valve assessment package: a feasibility study.

PubMed

Mahmood, Feroze; Karthik, Swaminathan; Subramaniam, Balachundhar; Panzica, Peter J; Mitchell, John; Lerner, Adam B; Jervis, Karinne; Maslow, Andrew D

2008-04-01

To study the feasibility of using 3-dimensional (3D) echocardiography in the operating room for mitral valve repair or replacement surgery. To perform geometric analysis of the mitral valve before and after repair. Prospective observational study. Academic, tertiary care hospital. Consecutive patients scheduled for mitral valve surgery. Intraoperative reconstruction of 3D images of the mitral valve. One hundred and two patients had 3D analysis of their mitral valve. Successful image reconstruction was performed in 93 patients-8 patients had arrhythmias or a dilated mitral valve annulus resulting in significant artifacts. Time from acquisition to reconstruction and analysis was less than 5 minutes. Surgeon identification of mitral valve anatomy was 100% accurate. The study confirms the feasibility of performing intraoperative 3D reconstruction of the mitral valve. This data can be used for confirmation and communication of 2-dimensional data to the surgeons by obtaining a surgical view of the mitral valve. The incorporation of color-flow Doppler into these 3D images helps in identification of the commissural or perivalvular location of regurgitant orifice. With improvements in the processing power of the current generation of echocardiography equipment, it is possible to quickly acquire, reconstruct, and manipulate images to help with timely diagnosis and surgical planning.

Left ventricular structural and functional changes evaluated by echocardiography and two-dimensional strain in patients with sickle cell disease.

PubMed

Bedirian, Ricardo; Soares, Andrea Ribeiro; Maioli, Maria Christina; de Medeiros, Jussara Fonseca Fernandes; Lopes, Agnaldo José; Castier, Marcia Bueno

2018-04-01

Patients with sickle cell disease have increased left ventricular size, which is not usually accompanied by changes in systolic function indexes. We assessed echocardiographic abnormalities present in patients with sickle cell anemia (SCA) and compared echocardiographic parameters to other sickle cell diseases (OSCD). A blind cross-sectional study with 60 patients with SCA and 16 patients with OSCD who underwent transthoracic echocardiography was performed. Echocardiographic findings were: left atrial volume index 47.7 ±11.5 ml/m² in SCA group and 31.7 ±8.42 ml/m² in OSCD group ( p < 0.001); left ventricular diastolic diameter index 3.47 ±0.37 cm/m² in SCA group and 2.97 ±0.41 cm/m² in OSCD group ( p < 0.001); left ventricular systolic diameter index 2.12 ±0.31 cm/m² in SCA group and 1.86 ±0.28 cm/m² in OSCD group ( p < 0.001). There were no differences in the left ventricular ejection fraction: 68.2 ±6.69% in SCA group and 67.1 ±6.21% in OSCD group ( p = 0.527). The ratio between mitral E wave and mean mitral annulus e' wave velocities was higher in the SCA group (7.72 ±1.54 vs. 6.70 ±1.65; p = 0.047). Mitral A wave correlated significantly with hemoglobin levels ( r = -0.340; p = 0.032). There was an increase of left ventricular and left atrial sizes in patients with SCA, compared to patients with OSCD, without changes in systolic or diastolic function in both groups. This could be due to the hyperkinetic state due to the more severe anemia in the SCA subjects.

Expression of transforming growth factor-beta1, -beta2 and -beta3 in normal and diseased canine mitral valves.

PubMed

Aupperle, H; März, I; Thielebein, J; Schoon, H-A

2008-01-01

The pathogenesis of chronic valvular disease (CVD) in dogs remains unclear, but activation and proliferation of valvular stromal cells (VSC) and their transdifferentiation into myofibroblast-like cells has been described. These alterations may be influenced by transforming growth factor-beta (TGF-beta), a cytokine involved in extracellular matrix (ECM) regulation and mesenchymal cell differentiation. The present study investigates immunohistochemically the expression of TGF-beta1, -beta2, -beta3 and smooth muscle alpha actin (alpha-SMA) in normal canine mitral valves (MVs) (n=10) and in the valves of dogs with mild (n=7), moderate (n=14) and severe (n=9) CVD. In normal mitral valves there was no expression of alpha-SMA but VSC displayed variable expression of TGF-beta1 (10% of VSC labelled), TGF-beta2 (1-5% labelled) and TGF-beta3 (50% labelled). In mild CVD the affected atrialis contain activated and proliferating alpha-SMA-positive VSC, which strongly expressed TGF-beta1 and -beta3, but only 10% of these cells expressed TGF-beta2. In unaffected areas of the leaflet there was selective increase in expression of TGF-beta1 and -beta3. In advanced CVD the activated subendothelial VSC strongly expressed alpha-SMA, TGF-beta1 and -beta3. Inactive VSC within the centre of the nodules had much less labelling for TGF-beta1 and -beta3. TGF-beta1 labelling was strong within the ECM. These data suggest that TGF-beta plays a role in the pathogenesis of CVD by inducing myofibroblast-like differentiation of VSC and ECM secretion. Changed haemodynamic forces and expression of matrix metalloproteinases (MMPs) may in turn regulate TGF-beta expression.

Annulus fibrosus of the mitral valve: reality or myth.

PubMed

Berdajs, Denis; Zünd, Gregor; Camenisch, Colette; Schurr, Ulrich; Turina, Marko I; Genoni, Michele

2007-01-01

Surgical repair of the mitral valve is in most cases limited to the posterior leaflet of the mitral valve and to the annulus fibrosus. The term annulus fibrosus is still used in anatomical and clinical terminology and is described as a cord like structure providing the attachment of the mitral vale. However, to date no evidence exists of a ring-or cord-like structure at this area. Herein, we describe the attachment of the mitral valve by using the macroscopical and microscopical techniques. The ventricular attachment of the posterior mitral valve leaflet was investigated in 10 human hearts. In dry dissected specimens, the intraventricular illumination was used to identify the attachment of the mitral valve to the left ventricular muscle. Using the histological techniques, we verified the position of the annulus fibrosus. The attachment of the posterior mitral valve leaflet is a band-like structure positioned between the left ventricular muscle and the left atrium. This fibrous band illustrates the morphological attachment of the mitral valve and, as thus, was interpreted as the annulus fibrosus of the mitral valve. Based on our data, no ring-like structure was found corresponding to the anatomical description of the annulus fibrosus, instead the band-like fibrous tissue was identified positioned between the mitral valve and the left ventricle. Histologicaly, we detected that this structure is part of the greater structural system that is directly connected to the membranous septum, to the left and right fibrous trigone and the attachment aortic root to the left ventricular muscle.

Percutaneous Transcatheter Mitral Valve Replacement: Patient-specific Three-dimensional Computer-based Heart Model and Prototyping.

PubMed

Vaquerizo, Beatriz; Theriault-Lauzier, Pascal; Piazza, Nicolo

2015-12-01

Mitral regurgitation is the most prevalent valvular heart disease worldwide. Despite the widespread availability of curative surgical intervention, a considerable proportion of patients with severe mitral regurgitation are not referred for treatment, largely due to the presence of left ventricular dysfunction, advanced age, and comorbid illnesses. Transcatheter mitral valve replacement is a promising therapeutic alternative to traditional surgical valve replacement. The complex anatomical and pathophysiological nature of the mitral valvular complex, however, presents significant challenges to the successful design and implementation of novel transcatheter mitral replacement devices. Patient-specific 3-dimensional computer-based models enable accurate assessment of the mitral valve anatomy and preprocedural simulations for transcatheter therapies. Such information may help refine the design features of novel transcatheter mitral devices and enhance procedural planning. Herein, we describe a novel medical image-based processing tool that facilitates accurate, noninvasive assessment of the mitral valvular complex, by creating precise three-dimensional heart models. The 3-dimensional computer reconstructions are then converted to a physical model using 3-dimensional printing technology, thereby enabling patient-specific assessment of the interaction between device and patient. It may provide new opportunities for a better understanding of the mitral anatomy-pathophysiology-device interaction, which is of critical importance for the advancement of transcatheter mitral valve replacement. Copyright © 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

The geometrical effect of different annuloplasty rings on mitral valve annulus.

PubMed

Al-Maisary, Sameer; Graser, Bastian; Engelhardt, Sandy; Wolf, Ivo; Karck, Matthias; DE Simone, Raffaele

2017-06-01

Different types of mitral annuloplasty rings are commercially available. The aim of this study was to investigate the effect of implantation of six types of annuloplasty rings on the geometry and dynamics of the mitral valve. Three-dimensional echocardiography images of 42 patients were acquired to visualize the mitral valve annulus. Virtual representations of six commercially available annuloplasty rings were matched to anatomical mitral annuli of each patient according to anterolateral-posteromedial diameter. The virtual displacement of each annuloplasty ring after the implantation was measured and compared with the other rings. Patients with severe mitral regurgitation had significantly dilated annuli according to anterolateral-posteromedial diameter, anterior-posterior diameter and to annulus circumference. Anterior and posterior heights of the mitral annuli and non-planarity angle showed no significant differences among different patients with different degree of mitral regurgitation. The ratio of anterior-posterior to anterolateral-posteromedial diameter was almost identical in all groups with identical annular shapes. The implantation of the Carpentier-Edwards Classic Annuloplasty Ring™ led to maximal displacement of mitral annulus, followed by the IM-Ring™, without a statistical significance. In contrary, the implantation of a MyxoETlogix Ring™ was associated with minimal displacement of mitral annulus throughout the groups, but without statistical significance. The implantation of different ring types in patients with different annuli shapes and dimensions did not lead to any significant change in the configuration of mitral annuli after the virtual implantation of the tested annuloplasty rings.

Vesicular glutamate transporter 1 and vesicular glutamate transporter 2 synapses on cholinergic neurons in the sublenticular gray of the rat basal forebrain: a double-label electron microscopic study.

PubMed

Hur, E E; Edwards, R H; Rommer, E; Zaborszky, L

2009-12-29

The basal forebrain (BF) comprises morphologically and functionally heterogeneous cell populations, including cholinergic and non-cholinergic corticopetal neurons that are implicated in sleep-wake modulation, learning, memory and attention. Several studies suggest that glutamate may be among inputs affecting cholinergic corticopetal neurons but such inputs have not been demonstrated unequivocally. We examined glutamatergic axon terminals in the sublenticular substantia innominata in rats using double-immunolabeling for vesicular glutamate transporters (Vglut1 and Vglut2) and choline acetyltransferase (ChAT) at the electron microscopic level. In a total surface area of 30,000 microm(2), we classified the pre- and postsynaptic elements of 813 synaptic boutons. Vglut1 and Vglut2 boutons synapsed with cholinergic dendrites, and occasionally Vglut2 axon terminals also synapsed with cholinergic cell bodies. Vglut1 terminals formed synapses with unlabeled dendrites and spines with equal frequency, while Vglut2 boutons were mainly in synaptic contact with unlabeled dendritic shafts and occasionally with unlabeled spines. In general, Vglut1 boutons contacted more distal dendritic compartments than Vglut2 boutons. About 21% of all synaptic boutons (n=347) detected in tissue that was stained for Vglut1 and ChAT were positive for Vglut1, and 14% of the Vglut1 synapses were made on cholinergic profiles. From separate cases stained for Vglut2 and ChAT, 35% of all synaptic boutons (n=466) were positive for Vglut2, and 23% of the Vglut2 synapses were made on cholinergic profiles. On average, Vglut1 boutons were significantly smaller than Vglut2 synaptic boutons. The Vglut2 boutons that synapsed cholinergic profiles tended to be larger than the Vglut2 boutons that contacted unlabeled, non-cholinergic postsynaptic profiles. The presence of two different subtypes of Vgluts, the size differences of the Vglut synaptic boutons, and their preference for different postsynaptic targets suggest that the action of glutamate on BF neurons is complex and may arise from multiple afferent sources.

Vglut1 and Vglut2 synapses on cholinergic neurons in the sublenticular gray of the rat basal forebrain: a double-label electron microscopic study

PubMed Central

Hur, Elizabeth E.; Edwards, Robert H.; Rommer, Erzsebet; Zaborszky, Laszlo

2009-01-01

The basal forebrain (BF) comprises morphologically and functionally heterogeneous cell populations, including cholinergic and non-cholinergic corticopetal neurons that are implicated in sleep-wake modulation, learning, memory and attention. Several studies suggest that glutamate may be among inputs affecting cholinergic corticopetal neurons but such inputs have not been demonstrated unequivocally. We examined glutamatergic axon terminals in the sublenticular substantia innominata in rats using double-immunolabeling for vesicular glutamate transporters (Vglut1 and Vglut2) and choline acetyltransferase (ChAT) at the electron microscopic level. In a total surface area of 30,000 μm2, we classified the pre- and postsynaptic elements of 813 synaptic boutons. Vglut1 and Vglut2 boutons synapsed with cholinergic dendrites, and occasionally Vglut2 axon terminals also synapsed with cholinergic cell bodies. Vglut1 terminals formed synapses with unlabeled dendrites and spines with equal frequency, while Vglut2 boutons were mainly in synaptic contact with unlabeled dendritic shafts and occasionally with unlabeled spines. In general, Vglut1 boutons contacted more distal dendritic compartments than Vglut2 boutons. About 21% of all synaptic boutons (n=347) detected in tissue that was stained for Vglut1 and ChAT were positive for Vglut1, and 14% of the Vglut1 synapses were made on cholinergic profiles. From separate cases stained for Vglut2 and ChAT, 35% of all synaptic boutons (n=466) were positive for Vglut2, and 23% of the Vglut2 synapses were made on cholinergic profiles. On average, Vglut1 boutons were significantly smaller than Vglut2 synaptic boutons. The Vglut2 boutons that synapsed cholinergic profiles tended to be larger than the Vglut2 boutons that contacted unlabeled, non-cholinergic postsynaptic profiles. The presence of two different subtypes of Vgluts, the size differences of the Vglut synaptic boutons, and their preference for different postsynaptic targets suggest that the action of glutamate on BF neurons is complex and may arise from multiple afferent sources. PMID:19778580

Functional role of ambient GABA in refining neuronal circuits early in postnatal development

PubMed Central

Cellot, Giada; Cherubini, Enrico

2013-01-01

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses. PMID:23964205

Quantification of mitral regurgitation using proximal isovelocity surface area method in dogs.

PubMed

Choi, Hojung; Lee, Kichang; Lee, Heechun; Lee, Youngwon; Chang, Dongwoo; Eom, Kidong; Youn, Hwayoung; Choi, Mincheol; Yoon, Junghee

2004-06-01

The present study was performed to determine the accuracy and reproducibility of calculating the mitral regurgitant orifice area with the proximal isovelocity surface area (PISA) method in dogs with experimental mitral regurgitation and in canine patients with chronic mitral insufficiency and to evaluate the effect of general anesthesia on mitral regurgitation. Eight adult, Beagle dogs for experimental mitral regurgitation and 11 small breed dogs with spontaneous mitral regurgitation were used. In 8 Beagle dogs, mild mitral regurgitation was created by disrupting mitral chordae or leaflets. Effective regurgitant orifice (ERO) area was measured by the PISA method and compared with the measurements simultaneously obtained by quantitative Doppler echocardiography 4 weeks after creation of mitral regurgitation. The same procedure was performed in 11 patients with isolated mitral regurgitation and in 8 Beagle dogs under two different protocols of general anesthesia. ERO and regurgitant stroke volume (RSV) by the PISA method correlated well with values by the quantitative Doppler technique with a small error in experimental dogs (r = 0.914 and r = 0.839) and 11 patients (r = 0.990 and r = 0.996). The isoflurane anesthetic echocardiography demonstrated a significant decrease of RSV, and there was no significant change in fractional shortening (FS), ERO area, LV end-diastolic and LV end-systolic volume. ERO area showed increasing tendency after ketamine-xylazine administration, but not statistically significant. RSV, LV end-systolic and LV end-diastolic volume increased significantly (p < 0.01), whereas FS significantly decreased (p < 0.01). The PISA method is accurate and reproducible in experimental mitral regurgitation model and in a clinical setting. ERO area is considered and preferred as a hemodynamic-nondependent factor than other traditional measurements.

Effects of Mitral Annulus Remodeling Following MitraClip Procedure on Reduction of Functional Mitral Regurgitation.

PubMed

Hidalgo, Francisco; Mesa, Dolores; Ruiz, Martín; Delgado, Mónica; Rodríguez, Sara; Pardo, Laura; Pan, Manuel; López, Amador; Romero, Miguel A; Suárez de Lezo, José

2016-11-01

The percutaneous mitral valve repair procedure (MitraClip) appears to reduce mitral annulus diameter in patients with functional mitral regurgitation, but the relationship between this and regurgitation severity has not been demonstrated. The aim of this study was to determine the effect of mitral annulus remodeling on the reduction of mitral regurgitation in patients with functional etiology. The study included all patients with functional mitral regurgitation treated with MitraClip at our hospital until January 2015. Echocardiogram (iE33 model, Philips) was performed in all patients immediately after device positioning. Changes in the mitral annulus correlated with mitral regurgitation severity, as assessed using the effective regurgitant orifice area. The study included 23 patients (age, 65±14 years; 74% men; left ventricular ejection fraction, 31%±13%; systolic pulmonary artery pressure, 47±10 mmHg). After the procedure, the regurgitant orifice area decreased by 0.30 cm 2 ±0.04 cm 2 (P<.0005), from a baseline of 0.49 cm 2 ±0.09 cm 2 . Anteroposterior diameter decreased by 3.14 mm±1.01 mm (P<.0005) from a baseline of 28.27 mm±4.9 mm, with no changes in the intercommissural diameter (0.50 mm±0.91 mm vs 40.68 mm±4.7 mm; P=.26). A significant association was seen between anteroposterior diameter reduction and regurgitant orifice area reduction (r=.49; P=.020). In patients with functional mitral regurgitation, the MitraClip device produces an immediate reduction in the anteroposterior diameter. This remodeling may be related to the reduction in mitral regurgitation. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Removal of area CA3 from hippocampal slices induces postsynaptic plasticity at Schaffer collateral synapses that normalizes CA1 pyramidal cell discharge.

PubMed

Dumas, Theodore C; Uttaro, Michael R; Barriga, Carolina; Brinkley, Tiffany; Halavi, Maryam; Wright, Susan N; Ferrante, Michele; Evans, Rebekah C; Hawes, Sarah L; Sanders, Erin M

2018-06-21

Neural networks that undergo acute insults display remarkable reorganization. This injury related plasticity is thought to permit recovery of function in the face of damage that cannot be reversed. Previously, an increase in the transmission strength at Schaffer collateral to CA1 pyramidal cell synapses was observed after long-term activity reduction in organotypic hippocampal slices. Here we report that, following acute preparation of adult rat hippocampal slices and surgical removal of area CA3, input to area CA1 was reduced and Schaffer collateral synapses underwent functional strengthening. This increase in synaptic strength was limited to Schaffer collateral inputs (no alteration to temporoammonic synapses) and acted to normalize postsynaptic discharge, supporting a homeostatic or compensatory response. Short-term plasticity was not altered, but an increase in immunohistochemical labeling of GluA1 subunits was observed in the stratum radiatum (but not stratum moleculare), suggesting increased numbers of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and a postsynaptic locus of expression. Combined, these data support the idea that, in response to the reduction in presynaptic activity caused by removal of area CA3, Schaffer collateral synapses undergo a relatively rapid increase in functional efficacy likely supported by insertion of more AMPARs, which maintains postsynaptic excitability in CA1 pyramidal neurons. This novel fast compensatory plasticity exhibits properties that would allow it to maintain optimal network activity levels in the hippocampus, a brain structure lauded for its ongoing experience-dependent malleability. Copyright © 2018 Elsevier B.V. All rights reserved.

Metabotropic glutamate receptors mGluR4 and mGluR8 regulate transmission in the lateral olfactory tract-piriform cortex synapse

PubMed Central

Jones, Paulianda J.; Xiang, Zixiu; Conn, P. Jeffrey

2008-01-01

The piriform cortex (PC) is the primary terminal zone of projections from the olfactory bulb, termed the lateral olfactory tract (LOT). The PC plays a critical role in processing of olfactory stimuli and is also a highly seizure prone area thought to be involved in some forms of temporal lobe epilepsy. Pharmacological and immunohistochemical studies provide evidence for the localization of various metabotropic glutamate receptors (GluRs) in the PC. We employed whole cell patch clamp recordings from PC pyramidal cells to determine the roles of group III mGluRs in modulating synaptic transmission at the LOT–PC synapse. The group III mGluR agonist, L-AP4, induced a concentration-dependent inhibition of synaptic transmission at the LOT-PC synapse at concentrations that activate mGluR4 and mGluR8, but not mGluR7 or other mGluR subtypes (EC50 = 473 nM). In addition, the selective mGluR8 agonist, DCPG (300 nM), also suppressed synaptic transmission at the LOT synapse. Furthermore, the inhibitory actions of L-AP4 and Z-cyclopentyl-AP4, a selective mGluR4 agonist, were potentiated by the mGluR4 positive allosteric modulator, PHCCC (30 µM). The high potency of L-AP4, combined with the observed effects of DCPG and PHCCC, suggests that both mGluR4 and mGluR8 play a role in the L-AP4-induced inhibition of synaptic transmission at the LOT-PC synapse. PMID:18625254

Coordinate synaptic mechanisms contributing to olfactory cortical adaptation.

PubMed

Best, Aaron R; Wilson, Donald A

2004-01-21

Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10-20 sec of the post-train recovery period and a longer lasting (approximately 120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the beta-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the beta (15-35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo.

Coordinate Synaptic Mechanisms Contributing to Olfactory Cortical Adaptation

PubMed Central

Best, Aaron R.; Wilson, Donald A.

2008-01-01

Anterior piriform cortex (aPCX) neurons rapidly filter repetitive odor stimuli despite relatively maintained input from mitral cells. This cortical adaptation is correlated with short-term depression of afferent synapses, in vivo. The purpose of this study was to elucidate mechanisms underlying this nonassociative neural plasticity using in vivo and in vitro preparations and to determine its role in cortical odor adaptation. Lateral olfactory tract (LOT)-evoked responses were recorded in rat aPCX coronal slices. Extracellular and intracellular potentials were recorded before and after simulated odor stimulation of the LOT. Results were compared with in vivo intracellular recordings from aPCX layer II/III neurons and field recordings in urethane-anesthetized rats stimulated with odorants. The onset, time course, and extent of LOT synaptic depression during both in vitro electrical and in vivo odorant stimulation methods were similar. Similar to the odor specificity of cortical odor adaptation in vivo, there was no evidence of heterosynaptic depression between independent inputs in vitro. In vitro evidence suggests at least two mechanisms contribute to this activity-dependent synaptic depression: a rapidly recovering presynaptic depression during the initial 10–20 sec of the post-train recovery period and a longer lasting (~120 sec) depression that can be blocked by the metabotropic glutamate receptor (mGluR) II/III antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG) and by the β-adrenergic receptor agonist isoproterenol. Importantly, in line with the in vitro findings, both adaptation of odor responses in the β (15–35 Hz) spectral range and the associated synaptic depression can also be blocked by intracortical infusion of CPPG in vivo. PMID:14736851

Re-evaluation of hypoplastic left heart syndrome from a developmental and morphological perspective.

PubMed

Crucean, A; Alqahtani, A; Barron, D J; Brawn, W J; Richardson, R V; O'Sullivan, J; Anderson, R H; Henderson, D J; Chaudhry, B

2017-08-10

Hypoplastic left heart syndrome (HLHS) covers a spectrum of rare congenital anomalies characterised by a non-apex forming left ventricle and stenosis/atresia of the mitral and aortic valves. Despite many studies, the causes of HLHS remain unclear and there are conflicting views regarding the role of flow, valvar or myocardial abnormalities in its pathogenesis, all of which were proposed prior to the description of the second heart field. Our aim was to re-evaluate the patterns of malformation in HLHS in relation to recognised cardiac progenitor populations, with a view to providing aetiologically useful sub-groupings for genomic studies. We examined 78 hearts previously classified as HLHS, with subtypes based on valve patency, and re-categorised them based on their objective ventricular phenotype. Three distinct subgroups could be identified: slit-like left ventricle (24%); miniaturised left ventricle (6%); and thickened left ventricle with endocardial fibroelastosis (EFE; 70%). Slit-like ventricles were always found in combination with aortic atresia and mitral atresia. Miniaturised left ventricles all had normally formed, though smaller aortic and mitral valves. The remaining group were found to have a range of aortic valve malformations associated with thickened left ventricular walls despite being described as either atresia or stenosis. The degree of myocardial thickening was not correlated to the degree of valvar stenosis. Lineage tracing in mice to investigate the progenitor populations that form the parts of the heart disrupted by HLHS showed that whereas Nkx2-5-Cre labelled myocardial and endothelial cells within the left and right ventricles, Mef2c-AHF-Cre, which labels second heart field-derived cells only, was largely restricted to the endocardium and myocardium of the right ventricle. However, like Nkx2-5-Cre, Mef2c-AHF-Cre lineage cells made a significant contribution to the aortic and mitral valves. In contrast, Wnt1-Cre made a major contribution only to the aortic valve. This suggests that discrete cardiac progenitors might be responsible for the patterns of defects observed in the distinct ventricular sub-groups. Only the slit-like ventricle grouping was found to map to the current nomenclature: the combination of mitral atresia with aortic atresia. It appears that slit-like and miniature ventricles also form discrete sub-groups. Thus, reclassification of HLHS into subgroups based on ventricular phenotype, might be useful in genetic and developmental studies in investigating the aetiology of this severe malformation syndrome.

Is mitral valve repair superior to replacement for chronic ischemic mitral regurgitation with left ventricular dysfunction?

PubMed Central

2010-01-01

Background This study was undertaken to compare mitral valve repair and replacement as treatments for ischemic mitral regurgitation (IMR) with left ventricular dysfunction (LVD). Specifically, we sought to determine whether the choice of mitral valve procedure affected survival, and discover which patients were predicted to benefit from mitral valve repair and which from replacement. Methods A total of 218 consecutive patients underwent either mitral valve repair (MVP, n = 112) or mitral valve replacement (MVR, n = 106). We retrospectively reviewed the clinical material, operation methods, echocardiography check during operation and follow-up. Patients details and follow-up outcomes were compared using multivariate and Kaplan-Meier analyses. Results No statistical difference was found between the two groups in term of intraoperative data. Early mortality was 3.2% (MVP 2.7% and MVR 3.8%). At discharge, Left ventricular end-systolic and end-diastolic diameter and left ventricular ejection fraction (LVEF) were improved more in the MVP group than MVR group (P < 0.05), however, in follow-up no statistically significant difference was observed between the MVR and MVP group (P > 0.05). Follow-up mitral regurgitation grade was significantly improved in the MVR group compared with the MVP group (P < 0.05). The Kaplan-Meier survival estimates at 1, 3, and 5 years were simlar between MVP and MVR group. Logistic regression revealed poor survival was associated with old age(#75), preoperative renal insufficiency and low left ventricular ejection fraction (< 30%). Conclusion Mitral valve repair is the procedure of choice in the majority of patients having surgery for severe ischemic mitral regurgitation with left ventricular dysfunction. Early results of MVP treatment seem to be satisfactory, but several lines of data indicate that mitral valve repair provided less long-term benefit than mitral valve replacement in the LVD patients. PMID:21059216

Mitral Valve Clip for Treatment of Mitral Regurgitation: An Evidence-Based Analysis

PubMed Central

Ansari, Mohammed T.; Ahmadzai, Nadera; Coyle, Kathryn; Coyle, Doug; Moher, David

2015-01-01

Background Many of the 500,000 North American patients with chronic mitral regurgitation may be poor candidates for mitral valve surgery. Objective The objective of this study was to investigate the comparative effectiveness, harms, and cost-effectiveness of percutaneous mitral valve repair using mitral valve clips in candidates at prohibitive risk for surgery. Data Sources We searched articles in MEDLINE, Embase, and the Cochrane Library published from 1994 to February 2014 for evidence of effectiveness and harms; for economic literature we also searched NHS EED and Tufts CEA registry. Grey literature was also searched. Review Methods Primary studies were sought from existing systematic reviews that had employed reliable search and screening methods. Newer studies were sought by searching the period subsequent to the last search date of the review. Two reviewers screened records and assessed study validity. We used the Cochrane risk of bias tool for randomized, generic assessment for non-randomized studies, and the Phillips checklist for economic studies. Results Ten studies including 1 randomized trial were included. The majority of the direct comparative evidence compared the mitral valve clip repair with surgery in patients not particularly at prohibitive surgical risk. Irrespective of degenerative or functional chronic mitral regurgitation etiology, evidence of effectiveness and harms is inconclusive and of very low quality. Very-low-quality evidence indicates that percutaneous mitral valve clip repair may provide a survival advantage, at least during the first 1 to 2 years, particularly in medically managed chronic functional mitral regurgitation. Because of limitations in the design of studies, the cost-effectiveness of mitral valve clips in patients at prohibitive risk for surgery also could not be established. Limitations Because of serious concerns of risk of bias, indirectness, and imprecision, evidence is of very low quality. Conclusions No meaningful conclusions can be drawn about the comparative effectiveness, harms, and cost-effectiveness of mitral valve clips in the population with chronic mitral regurgitation who are at prohibitive risk for surgery. PMID:26379810

Efficacy of chordal cutting in alleviating ischemic mitral regurgitation: insights from 3-dimensional echocardiography

PubMed Central

Sai-Sudhakar, Chittoor B; Vandse, Rashmi; Armen, Todd A; Bickle, Katherine M; Nathan, Nadia S

2007-01-01

Background Ischemic mitral regurgitation often complicates severe ischemic heart disease and adversely affects the prognosis in these patients. There is wide variation in the clinical spectrum of ischemic mitral regurgitation due to varying location and chronicity of ischemia and anomalies in annular and ventricular remodeling. As a result, there is lack of consensus in treating these patients. Treatment has to be individualized for each patient. Most of the available surgical options do not consistently correct this condition in all the patients. Chordal cutting is one of the newer surgical approaches in which cutting a limited number of critically positioned basal chordae have found success by relieving the leaflet tethering and thereby improving the coaptation of leaflets. Three-dimensional echocardiography is a potentially valuable tool in identifying the specific pattern of tethering and thus the suitability of this procedure in a given clinical scenario. Case Presentation A 66-year-old man with cardiomyopathy and ischemic mitral regurgitation presented to us with the features of congestive heart failure. The three-dimensional echocardiography revealed severe mitral regurgitation associated with the tethering of the lateral (P1) and medial (P3) scallops of the posterior leaflet of the mitral valve due to secondary chordal attachments. The ejection fraction was only 15% with severe global systolic and diastolic dysfunction. Mitral regurgitation was successfully corrected with mitral annuloplasty and resection of the secondary chordae tethering the medial and lateral scallops of the posterior leaflet of the mitral valve. Conclusion Cutting the second order chordae along with mitral annuloplasty could be a novel method to remedy Ischemic mitral regurgitation by relieving the tethering of the valve leaflets. The preoperative three-dimensional echocardiography should be considered in all patients with Ischemic mitral regurgitation to assess the complex three-dimensional interactions between the mitral valve apparatus and the left ventricle. This aids in timely surgical planning. PMID:17894872

Efficacy of chordal cutting in alleviating ischemic mitral regurgitation: insights from 3-dimensional echocardiography.

PubMed

Sai-Sudhakar, Chittoor B; Vandse, Rashmi; Armen, Todd A; Bickle, Katherine M; Nathan, Nadia S

2007-09-25

Ischemic mitral regurgitation often complicates severe ischemic heart disease and adversely affects the prognosis in these patients. There is wide variation in the clinical spectrum of ischemic mitral regurgitation due to varying location and chronicity of ischemia and anomalies in annular and ventricular remodeling. As a result, there is lack of consensus in treating these patients. Treatment has to be individualized for each patient. Most of the available surgical options do not consistently correct this condition in all the patients. Chordal cutting is one of the newer surgical approaches in which cutting a limited number of critically positioned basal chordae have found success by relieving the leaflet tethering and thereby improving the coaptation of leaflets. Three-dimensional echocardiography is a potentially valuable tool in identifying the specific pattern of tethering and thus the suitability of this procedure in a given clinical scenario. A 66-year-old man with cardiomyopathy and ischemic mitral regurgitation presented to us with the features of congestive heart failure. The three-dimensional echocardiography revealed severe mitral regurgitation associated with the tethering of the lateral (P1) and medial (P3) scallops of the posterior leaflet of the mitral valve due to secondary chordal attachments. The ejection fraction was only 15% with severe global systolic and diastolic dysfunction. Mitral regurgitation was successfully corrected with mitral annuloplasty and resection of the secondary chordae tethering the medial and lateral scallops of the posterior leaflet of the mitral valve. Cutting the second order chordae along with mitral annuloplasty could be a novel method to remedy Ischemic mitral regurgitation by relieving the tethering of the valve leaflets. The preoperative three-dimensional echocardiography should be considered in all patients with Ischemic mitral regurgitation to assess the complex three-dimensional interactions between the mitral valve apparatus and the left ventricle. This aids in timely surgical planning.

Preoperative planning with three-dimensional reconstruction of patient's anatomy, rapid prototyping and simulation for endoscopic mitral valve repair.

PubMed

Sardari Nia, Peyman; Heuts, Samuel; Daemen, Jean; Luyten, Peter; Vainer, Jindrich; Hoorntje, Jan; Cheriex, Emile; Maessen, Jos

2017-02-01

Mitral valve repair performed by an experienced surgeon is superior to mitral valve replacement for degenerative mitral valve disease; however, many surgeons are still deterred from adapting this procedure because of a steep learning curve. Simulation-based training and planning could improve the surgical performance and reduce the learning curve. The aim of this study was to develop a patient-specific simulation for mitral valve repair and provide a proof of concept of personalized medicine in a patient prospectively planned for mitral valve surgery. A 65-year old male with severe symptomatic mitral valve regurgitation was referred to our mitral valve heart team. On the basis of three-dimensional (3D) transoesophageal echocardiography and computed tomography, 3D reconstructions of the patient's anatomy were constructed. By navigating through these reconstructions, the repair options and surgical access were chosen (minimally invasive repair). Using rapid prototyping and negative mould fabrication, we developed a process to cast a patient-specific mitral valve silicone replica for preoperative repair in a high-fidelity simulator. Mitral valve and negative mould were printed in systole to capture the pathology when the valve closes. A patient-specific mitral valve silicone replica was casted and mounted in the simulator. All repair techniques could be performed in the simulator to choose the best repair strategy. As the valve was printed in systole, no special testing other than adjusting the coaptation area was required. Subsequently, the patient was operated, mitral valve pathology was validated and repair was successfully done as in the simulation. The patient-specific simulation and planning could be applied for surgical training, starting the (minimally invasive) mitral valve repair programme, planning of complex cases and the evaluation of new interventional techniques. The personalized medicine could be a possible pathway towards enhancing reproducibility, patient's safety and effectiveness of a complex surgical procedure. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Strychnine-blocked glycine receptor is removed from synapses by a shift in insertion/degradation equilibrium.

PubMed

Rasmussen, Hanne; Rasmussen, Trine; Triller, Antoine; Vannier, Christian

2002-02-01

The long-term inhibition by strychnine of glycine receptor activity in neurons provokes the receptor's selective intracellular accumulation and disappearance from synapses. This could result either from a disruption of the postsynaptic anchoring of the receptor or from an arrest of its exocytic transport. In this study we combined biochemical and fluorescence microscopy analyses to determine on a short time scale the fate of the strychnine-inactivated glycine receptor. Quantification of the cellular content of receptor showed that the rapid accumulation depends on protein synthesis. Cell surface biotinylation of neurons demonstrated that strychnine did not accelerate the turnover rate of the receptor. Labeling of endosomes indicated that, in strychnine-treated cells, the accumulated receptor is not blocked in the endosomal transport pathway. Taken together, these results indicate that strychnine does not destabilize the postsynaptic receptor but triggers its disappearance from synapses by a nondegradative sequestration of newly synthesized molecules in a nonendocytic compartment. (C)2002 Elsevier Science (USA).

Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective.

PubMed

Macht, Victoria A; Reagan, Lawrence P

2018-04-01

The development of the organism is a critical variable which influences the magnitude, duration, and reversibility of the effects of chronic stress. Such factors are relevant to the prefrontal cortex (PFC), as this brain region is the last to mature, the first to decline, and is highly stress-sensitive. Therefore, this review will examine the intersection between the nervous system and immune system at glutamatergic synapses in the PFC across three developmental periods: adolescence, adulthood, and aging. Glutamatergic synapses are tightly juxtaposed with microglia and astrocytes, and each of these cell types exhibits their own developmental trajectory. Not only does chronic stress differentially impact each of these cell types across development, but chronic stress also alters intercellular communication within this quad-partite synapse. These observations suggest that developmental shifts in both neural and immune function across neurons, microglia, and astrocytes mediate shifting effects of chronic stress on glutamatergic transmission. Copyright © 2018 Elsevier Inc. All rights reserved.

Formation and organization of protein domains in the immunological synapse

NASA Astrophysics Data System (ADS)

Carlson, Andreas; Mahadevan, L.

2014-11-01

The cellular basis for the adaptive immune response during antigen recognition relies on a specialized protein interface known as the immunological synapse. Here, we propose a minimal mathematical model for the dynamics of the IS that encompass membrane mechanics, hydrodynamics and protein kinetics. Simple scaling laws describe the dynamics of protein clusters as a function of membrane stiffness, rigidity of the adhesive proteins, and fluid flow in the synaptic cleft. Numerical simulations complement the scaling laws by quantifying the nucleation, growth and stabilization of proteins domains on the size of the cell. Direct comparison with experiment suggests that passive dynamics suffices to describe the short-time formation and organization of protein clusters, while the stabilization and long time dynamics of the synapse is likely determined by active cytoskeleton processes triggered by receptor binding. Our study reveals that the fluid flow generated by the interplay between membrane deformation and protein binding kinetics can assist immune cells in regulating protein sorting.

Mitral annulus size links ventricular dilatation to functional mitral regurgitation.

PubMed

Popović, Zoran B; Martin, Maureen; Fukamachi, Kiyotaka; Inoue, Masahiro; Kwan, Jun; Doi, Kazuyoshi; Qin, Jian Xin; Shiota, Takahiro; Garcia, Mario J; McCarthy, Patrick M; Thomas, James D

2005-09-01

We compared the impact of annulus size and valve deformation (tethering) on mitral regurgitation in the animal dilated cardiomyopathy model, and assessed if acute left ventricular volume changes affect mitral annulus dimensions. We performed 3-dimensional echocardiography in 30 open-chest dogs with pacing-induced cardiomyopathy. Mitral annulus area was calculated from its two orthogonal diameters, whereas valve tethering was quantified by valve tenting area measurement. Mitral valve regurgitant volume showed the highest correlation with annulus area (r = 0.64, P < .001), left atrial volume (r = 0.40, P < .01), and left ventricular end-diastolic volume (r = 0.37, P < .01). Regurgitant volume showed poorer correlation with valve tethering in both septolateral and intercommissural planes (r = 0.35 and r = 0.31, P < .05 for both). Annulus dimensions correlated with acute changes of left ventricular end-diastolic volume (r = 0.68, P = .002). Mitral annulus dilation is the strongest predictor of functional mitral regurgitation in this animal dilated cardiomyopathy model.

Mechanism of reduction of mitral regurgitation with vasodilator therapy.

PubMed

Yoran, C; Yellin, E L; Becker, R M; Gabbay, S; Frater, R W; Sonnenblick, E H

1979-04-01

Acute mitral regurgitation was produced in six open chest dogs by excising a portion of the anterior valve leaflet. Electromagnetic flow probes were placed in the left atrium around the mitral anulus and in the ascending aorta to determine phasic left ventricular filling volume, regurgitant volume and stroke volume. The systolic pressure gradient was calculated from simultaneously measured high fidelity left atrial and left ventricular pressures. The effective mitral regurgitant orifice area was calculated from Gorlin's hydraulic equation. Infusion of nitroprusside resulted in a significant reduction in mitral regurgitation. No significant change occurred in the systolic pressure gradient between the left ventricle and the left atrium because both peak left ventricular pressure and left atrial pressure were reduced. The reduction of mitral regurgitation was largely due to reduction in the size of the mitral regurgitant orifice. Reduction of ventricular volume rather than the traditional concept of reduction of impedance of left ventricular ejection may explain the effects of vasodilators in reducing mitral regurgitation.

Spaceflight-induced synaptic modifications within hair cells of the mammalian utricle.

PubMed

Sultemeier, David R; Choy, Kristel R; Schweizer, Felix E; Hoffman, Larry F

2017-06-01

Exposure to the microgravity conditions of spaceflight alleviates the load normally imposed by the Earth's gravitational field on the inner ear utricular epithelia. Previous ultrastructural investigations have shown that spaceflight induces an increase in synapse density within hair cells of the rat utricle. However, the utricle exhibits broad physiological heterogeneity across different epithelial regions, and it is unknown whether capabilities for synaptic plasticity generalize to hair cells across its topography. To achieve systematic and broader sampling of the epithelium than was previously conducted, we used immunohistochemistry and volumetric image analyses to quantify synapse distributions across representative utricular regions in specimens from mice exposed to spaceflight (a 15-day mission of the space shuttle Discovery). These measures were compared with similarly sampled Earth-bound controls. Following paraformaldehyde fixation and microdissection, immunohistochemistry was performed on intact specimens to label presynaptic ribbons (anti-CtBP2) and postsynaptic receptor complexes (anti-Shank1A). Synapses were identified as closely apposed pre- and postsynaptic puncta. Epithelia from horizontal semicircular canal cristae served as "within-specimen" controls, whereas utricles and cristae from Earth-bound cohorts served as experimental controls. We found that synapse densities decreased in the medial extrastriolae of microgravity specimens compared with experimental controls, whereas they were unchanged in the striolae and horizontal cristae from the two conditions. These data demonstrate that structural plasticity was topographically localized to the utricular region that encodes very low frequency and static changes in linear acceleration, and illuminates the remarkable capabilities of utricular hair cells for synaptic plasticity in adapting to novel gravitational environments. NEW & NOTEWORTHY Spaceflight imposes a radically different sensory environment from that in which the inner ear utricle normally operates. We investigated synaptic modifications in utricles from mice flown aboard a space shuttle mission. Structural synaptic plasticity was detected in the medial extrastriola, a region associated with encoding static head position, as decreased synapse density. These results are remarkably congruent with a recent report of decreased utricular function in astronauts immediately after returning from the International Space Station. Copyright © 2017 the American Physiological Society.

A STED-FLIM microscope applied to imaging the natural killer cell immune synapse

NASA Astrophysics Data System (ADS)

Lenz, M. O.; Brown, A. C. N.; Auksorius, E.; Davis, D. M.; Dunsby, C.; Neil, M. A. A.; French, P. M. W.

2011-03-01

We present a stimulated emission depletion (STED) fluorescence lifetime imaging (FLIM) microscope, excited by a microstructured optical fibre supercontinuum source that is pumped by a femtosecond Ti:Sapphire-laser, which is also used for depletion. Implemented using a piezo-scanning stage on a laser scanning confocal fluorescence microscope system with FLIM realised using time correlated single photon counting (TCSPC), this provides convenient switching between confocal and STED-FLIM with spatial resolution down to below 60 nm. We will present our design considerations to make a robust instrument for biological applications including a comparison between fixed phase plate and spatial light modulator (SLM) approaches to shape the STED beam and the correlation of STED and confocal FLIM microscopy. Following our previous application of FLIM-FRET to study intercellular signalling at the immunological synapse (IS), we are employing STED microscopy to characterize the spatial distribution of cellular molecules with subdiffraction resolution at the IS. In particular, we are imaging cytoskeletal structure at the Natural Killer cell activated immune synapse. We will also present our progress towards multilabel STED microscopy to determine how relative spatial molecular organization, previously undetectable by conventional microscopy techniques, is important for NK cell cytotoxic function. Keywords: STED, Stimulated Emission Depletion Microscopy, Natural Killer (NK) cell, Fluorescence lifetime imaging, FLIM, Super resolution microscopy.

Synaptic communication between neurons and NG2+ cells.

PubMed

Paukert, Martin; Bergles, Dwight E

2006-10-01

Chemical synaptic transmission provides the basis for much of the rapid signaling that occurs within neuronal networks. However, recent studies have provided compelling evidence that synapses are not used exclusively for communication between neurons. Physiological and anatomical studies indicate that a distinct class of glia known as NG2(+) cells also forms direct synaptic junctions with both glutamatergic and GABAergic neurons. Glutamatergic signaling can influence intracellular Ca(2+) levels in NG2(+) cells by activating Ca(2+) permeable AMPA receptors, and these inputs can be potentiated through high frequency stimulation. Although the significance of this highly differentiated form of communication remains to be established, these neuro-glia synapses might enable neurons to influence rapidly the behavior of this ubiquitous class of glial progenitors.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

PubMed

Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

2012-03-01

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Vortex formation and instability in the left ventricle

NASA Astrophysics Data System (ADS)

Le, Trung Bao; Sotiropoulos, Fotis; Coffey, Dane; Keefe, Daniel

2012-09-01

We study the formation of the mitral vortex ring during early diastolic filling in a patient-specific left ventricle (LV) using direct numerical simulation. The geometry of the left ventricle is reconstructed from Magnetic Resonance Imaging (MRI) data of a healthy human subject. The left ventricular kinematics is modeled via a cell-based activation methodology, which is inspired by cardiac electro-physiology and yields physiologic LV wall motion. In the fluid dynamics videos, we describe in detail the three-dimensional structure of the mitral vortex ring, which is formed during early diastolic filling. The ring starts to deform as it propagates toward the apex of the heart and becomes inclined. The trailing secondary vortex tubes are formed as the result of interaction between the vortex ring and the LV wall. These vortex tubes wrap around the circumference and begin to interact with and destabilize the mitral vortex ring. At the end of diastole, the vortex ring impinges on the LV wall and the large-scale intraventricular flow rotates in clockwise direction. We show for the first time that the mitral vortex ring evolution is dominated by a number of vortex-vortex and vortex-wall interactions, including lateral straining and deformation of vortex ring, the interaction of two vortex tubes with unequal strengths, helicity polarization of vortex tubes and twisting instabilities of the vortex cores.

Mitral stenosis and percutaneous mitral valvuloplasty (part 1).

PubMed

Guérios, Enio E; Bueno, Ronaldo; Nercolini, Deborah; Tarastchuk, José; Andrade, Paulo; Pacheco, Alvaro; Faidiga, Alysson; Negrao, Stefan; Barbosa, Antonio

2005-07-01

Although the incidence and severity of rheumatic mitral stenosis have declined in developed countries, the disease is still highly prevalent in many of the poorer and most densely populated areas of the globe, remaining a major public health issue and reflecting the socioeconomic status of the region. In the last 30 years, mitral stenosis therapy has undergone a reorientation with the introduction of percutaneous mitral valvuloplasty. This manuscript is an updated review of percutaneous dilation of mitral stenosis in its different aspects, encompassing traditional techniques, technical innovations, the most significant case loads worldwide, an analysis of the procedure as well as immediate and late outcomes.

Percutaneous Mitral Valvuloplasty in a Mid-Term Pregnant Woman with Severe Rheumatic Mitral Stenosis

PubMed Central

Lee, Myoung Mook; Sohn, Dae-Won; Oh, Byung Hee; Kim, Jung Goo; Park, Young Bae; Choi, Yun Shik; Seo, Jung Don; Lee, Young Woo

1992-01-01

A 28-year-old woman with severe mitral stenosis underwent percutaneous mitral valvuloplasty at 26 weeks’ gestation. Balloon dilation using a double 18-18 mm balloon resulted in improvement in mean mitral pressure gradient (32 to 8 mmHg) and in calculated mitral valve area (0.9 to 2.4 cm2) without complications and any evidence of fetal distress during procedures with an estimated radiation exposure to the fetus of 0.13 rem. This procedure resulted in the disappearance of symptoms of congestive heart failure and allowed for normal full term spontaneous delivery of a 3.51 kg boy without any complication. PMID:1477032

Multiplanar visualization in 3D transthoracic echocardiography for precise delineation of mitral valve pathology.

PubMed

Kuppahally, Suman S; Paloma, Allan; Craig Miller, D; Schnittger, Ingela; Liang, David

2008-01-01

A novel multiplanar reformatting (MPR) technique in three-dimensional transthoracic echocardiography (3D TTE) was used to precisely localize the prolapsed lateral segment of posterior mitral valve leaflet in a patient symptomatic with mitral valve prolapse (MVP) and moderate mitral regurgitation (MR) before undergoing mitral valve repair surgery. Transesophageal echocardiography was avoided based on the findings of this new technique by 3D TTE. It was noninvasive, quick, reproducible and reliable. Also, it did not need the time-consuming reconstruction of multiple cardiac images. Mitral valve repair surgery was subsequently performed based on the MPR findings and corroborated the findings from the MPR examination.

Myectomy and LA-to-LV Conduit for Severe Calcific Mitral Stenosis and Hypertrophic Cardiomyopathy.

PubMed

Meghji, Zahara; Nguyen, Anita; Geske, Jeffrey B; Schaff, Hartzell V

2018-02-26

Severe calcific mitral valve stenosis can rarely occur concomitantly with obstructive hypertrophic cardiomyopathy. In these patients, surgical decalcification of the stenotic mitral valve followed by mitral valve replacement carries significant operative risk and may result in paravalvular leakage, atrioventricular groove disruption, and excessive bleeding. We report the first 2 cases of obstructive hypertrophic cardiomyopathy with severe calcific mitral valve stenosis successfully treated with concomitant transaortic septal myectomy and bypass of the stenotic mitral valve using a valved left atrium to left ventricular conduit. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Snare-assisted anterograde balloon mitral and aortic valvotomy using Inoue balloon catheter.

PubMed

Krishnan, Mangalath N; Syamkumar, M D; Sajeev, C G; Venugopal, K; Johnson, Francis; Vinaykumar, D; Velayudhan, C C; Jayakumar, T G

2007-01-02

We performed concurrent antegrade mitral and aortic valvotomy using Inoue dilatation catheter in 3 cases of combined rheumatic mitral and aortic stenosis. Following mitral valvotomy by standard procedure, aortic valve was crossed with the help of a floatation catheter. Stiff long length guide wire was fixed in descending aorta using a snare. Inoue catheter was threaded over the wire across the aortic valve and aortic valvotomy completed. Mitral valve area increased from mean 1 cm2 to 2 cm2; aortic gradient dropped from mean of 97 mm to 36 mm. Concurrent anterograde balloon mitral and aortic valvotomy may be effective and safe.

The "Polar Light Sign" is a useful tool to detect discrete membranous supravalvular mitral stenosis.

PubMed

Hertwig, Christine; Haas, Nikolaus A; Habash, Sheeraz; Hanslik, Andreas; Kececioglu, Deniz; Sandica, Eugen; Laser, Kai-Thorsten

2015-02-01

Mitral valve stenosis caused by a discrete supravalvular membrane is a rare congenital malformation haemodynamically leading to significant mitral valve stenosis. When the supravalvular mitral stenosis consists of a discrete supravalvular membrane adherent to the mitral valve, it is usually not clearly detectable by routine echocardiography. We report about the typical echocardiographic finding in three young patients with this rare form of a discrete membranous supravalvular stenosis caused by a membrane adherent to the mitral valve. These cases present a typical echocardiographic feature in colour Doppler generated by the pathognomonic supramitral flow acceleration. Whereas typical supravalvular mitral stenosis caused by cor triatriatum or a clearly visible supravalvular ring is easily detectable by echocardiography, a discrete supravalvular membrane adjacent to the mitral valve leaflets resembling valvular mitral stenosis is difficult to differentiate by routine echocardiography. In our opinion, this colour phenomenon does resemble the visual impression of polar lights in the northern hemisphere; owing to its typical appearance, it may therefore be named as "Polar Light Sign". This phenomenon may help to detect this anatomical entity by echocardiography in time and therefore improve the prognosis for repair.

Mitral valve replacement with preservation of the subvalvular apparatus.

PubMed

Reardon, M J; David, T E

1999-03-01

The introduction of the Starr-Edwards valve allowed complete replacement of diseased left-sided heart valves. With improved cardiopulmonary bypass, myocardial protection, and surgical techniques the mortality rate from aortic valve replacement decreased substantially, whereas the mortality rate from mitral valve replacement remained high, largely because of low cardiac output syndrome. Increasing use of mitral valve repair techniques resulted in a marked decrease in short-term and long-term morbidity and mortality when treating patients with mitral regurgitation. Some believed that this resulted from maintenance of the mitral annular papillary muscle continuity during mitral valve repair. Subsequent experimental and clinical studies have validated the positive short-term and long-term effects of maintaining the integrity of the mitral valve subvalvular apparatus. This article considers the history of the clinical use of preservation of the subvalvular apparatus, the physiologic studies examining this concept, and the clinical data available on its use. It also examines the following: 1) mitral stenosis versus mitral regurgitation and the preservation of the subvalvular apparatus; 2) whether the anterior, posterior, or both areas of the subvalvular apparatus should be preserved; and 3) the surgical techniques for the preservation of the subvalvular apparatus and valve implantation.

Balloon mitral valvuloplasty during pregnancy--our experience.

PubMed

Salomé, Nuno; Dias, Carla C; Ribeiro, José; Gonçalves, Manuel; Fonseca, Conceição; Ribeiro, Vasco Gama

2002-12-01

Mitral stenosis is the most common valvular heart lesion found in pregnancy. When severe, it leads to significant maternal and fetal morbidity and mortality, since the hemodynamic adaptations to pregnancy are badly tolerated. Pregnancy can lead to development of heart failure in patients with asymptomatic or even unknown mitral stenosis, as a result of the increased mitral valve pressure gradient caused by the physiologic increase in heart rate and blood volume in pregnancy. When symptoms persist despite optimal medical therapy, the poor prognosis justifies the correction of mitral stenosis during pregnancy. To present our experience in treating severe mitral stenosis in women who develop severe heart failure during pregnancy, using percutaneous balloon mitral valvuloplasty. From 1996 to March 2002, in our department, 47 balloon mitral valvuloplasties were successfully performed in women, three of them pregnant. These were patients with congestive heart failure, New York Heart Association (NYHA) functional class III or IV, at the end of the second trimester of pregnancy, who did not respond positively to drug treatment with diuretics and digitalis. We performed percutaneous balloon mitral valvuloplasty using the Inoue technique in the three pregnant patients, with success, at around 25 weeks of gestation. After the procedure, the patients showed clinical improvement, returning to the NYHA functional class that they were in before becoming pregnant (I-II). The previous mitral valve area was 0.9-1.2 cm2, nearly doubling after valvuloplasty. Mean left atrial pressure decreased on average by 42%, and the maximum pressure (V wave) decreased on average by 40%. The mitral valve pressure gradient decreased from 15, 10 and 28 mmHg to 7, 5 and 5 mmHg after valvuloplasty. During the procedure there were no maternal or fetal complications. All patients were discharged 24 to 48 h after valvuloplasty, continuing their pregnancies without complications. One woman had vaginal delivery, and the other two had cesarean sections at 35 weeks of gestation, all without complications with healthy newborns that developed normally. In follow-up, one patient who had moderate mitral regurgitation after valvuloplasty developed severe mitral regurgitation, requiring surgical correction after two years. In pregnant patients who have severe mitral stenosis and persistent congestive heart failure symptoms despite conventional medical treatment, when feasible, percutaneous balloon mitral valvuloplasty is the best treatment.

Role for a Novel Usher Protein Complex in Hair Cell Synaptic Maturation

PubMed Central

Zallocchi, Marisa; Meehan, Daniel T.; Delimont, Duane; Rutledge, Joseph; Gratton, Michael Anne; Flannery, John; Cosgrove, Dominic

2012-01-01

The molecular mechanisms underlying hair cell synaptic maturation are not well understood. Cadherin-23 (CDH23), protocadherin-15 (PCDH15) and the very large G-protein coupled receptor 1 (VLGR1) have been implicated in the development of cochlear hair cell stereocilia, while clarin-1 has been suggested to also play a role in synaptogenesis. Mutations in CDH23, PCDH15, VLGR1 and clarin-1 cause Usher syndrome, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa. Here we show developmental expression of these Usher proteins in afferent spiral ganglion neurons and hair cell synapses. We identify a novel synaptic Usher complex comprised of clarin-1 and specific isoforms of CDH23, PCDH15 and VLGR1. To establish the in vivo relevance of this complex, we performed morphological and quantitative analysis of the neuronal fibers and their synapses in the Clrn1−/− mouse, which was generated by incomplete deletion of the gene. These mice showed a delay in neuronal/synaptic maturation by both immunostaining and electron microscopy. Analysis of the ribbon synapses in Ames waltzerav3J mice also suggests a delay in hair cell synaptogenesis. Collectively, these results show that, in addition to the well documented role for Usher proteins in stereocilia development, Usher protein complexes comprised of specific protein isoforms likely function in synaptic maturation as well. PMID:22363448

CD28 and lipid rafts coordinate recruitment of Lck to the immunological synapse of human T lymphocytes.

PubMed

Tavano, Regina; Gri, Giorgia; Molon, Barbara; Marinari, Barbara; Rudd, Christopher E; Tuosto, Loretta; Viola, Antonella

2004-11-01

In T lymphocytes, the Src family kinase Lck associates lipid rafts and accumulates at the immunological synapse (IS) during T cell stimulation by APCs. Using CD4- or CD28-deficient murine T cells, it was suggested that recruitment of Lck to the IS depends on CD4, whereas CD28 sustains Lck activation. However, in human resting T cells, CD28 is responsible for promoting recruitment of lipid rafts to the IS by an unknown mechanism. Thus, we performed a series of experiments to determine 1) whether Lck is recruited to the IS through lipid rafts; and 2) whether Lck recruitment to the IS of human resting T cells depends on CD4 or on CD28 engagement. We found that CD28, but not CD4, stimulation induced recruitment of Lck into detergent-resistant domains as well as its accumulation at the IS. We also found that Lck recruitment to the IS depends on the CD28 COOH-terminal PxxPP motif. Thus, the CD28-3A mutant, generated by substituting the prolines in positions 208, 211, and 212 with alanines, failed to induce Lck and lipid raft accumulation at the synapse. These results indicate that CD28 signaling orchestrates both Lck and lipid raft recruitment to the IS to amplify T cell activation.

Patch enlargement of the aortic and mitral valve rings with aortic and mitral double valve replacement. Experimental study.

PubMed

Manouguian, S; Abu-Aishah, N; Neitzel, J

1979-09-01

The experimental results of patch enlargement of the aortic and mitral valve rings with aortic and mitral double valve replacement are reported. The operative technique of this new surgical method is described and the indications are discussed.

Mechanisms for Cell-to-Cell Transmission of HIV-1

PubMed Central

Bracq, Lucie; Xie, Maorong; Benichou, Serge; Bouchet, Jérôme

2018-01-01

While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia-like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues. PMID:29515578

Calcium signaling in taste cells: regulation required.

PubMed

Medler, Kathryn F

2010-11-01

Peripheral taste receptor cells depend on distinct calcium signals to generate appropriate cellular responses that relay taste information to the central nervous system. Some taste cells have conventional chemical synapses and rely on calcium influx through voltage-gated calcium channels. Other taste cells lack these synapses and depend on calcium release from stores to formulate an output signal through a hemichannel. Despite the importance of calcium signaling in taste cells, little is known about how these signals are regulated. This review summarizes recent studies that have identified 2 calcium clearance mechanisms expressed in taste cells, including mitochondrial calcium uptake and sodium/calcium exchangers (NCXs). These studies identified a unique constitutive calcium influx that contributes to maintaining appropriate calcium homeostasis in taste cells and the role of the mitochondria and exchangers in this process. The additional role of NCXs in the regulation of evoked calcium responses is also discussed. Clearly, calcium signaling is a dynamic process in taste cells and appears to be more complex than has previously been appreciated.

Immediate Outcome of Balloon Mitral Valvuloplasty with JOMIVA Balloon during Pregnancy

PubMed Central

Ramasamy, Ramona; Kaliappan, Tamilarasu; Gopalan, Rajendiran; Palanimuthu, Ramasmy; Anandhan, Premkrishna

2017-01-01

Introduction Rheumatic mitral stenosis is the most common Valvular Heart Disease encountered during pregnancy. Balloon Mitral Valvuloplasty (BMV) is one of the treatment option available if the symptoms are refractory to the medical management and the valve anatomy is suitable for balloon dilatation. BMV with Inoue balloon is the most common technique being followed worldwide. Over the wire BMV is a modified technique using Joseph Mitral Valvuloplasty (JOMIVA) balloon catheter which is being followed in certain centres. Aim To assess the immediate post procedure outcome of over the wire BMV with JOMIVA balloon. Materials and Methods Clinical and echocardiographic parameters of pregnant women with significant mitral stenosis who underwent elective BMV with JOMIVA balloon in our institute from 2005 to 2015 were analysed retrospectively. Severity of breathlessness (New York Heart Association Functional Class), and duration of pregnancy was included in the analysis. Pre procedural echocardiographic parameters which included severity of mitral stenosis and Wilkin’s scoring were analysed. Clinical, haemodynamic and echocardiographic outcomes immediately after the procedure were analysed. Results Among the patients who underwent BMV in our Institute 38 were pregnant women. Twenty four patients (63%) were in New York Heart Association (NYHA) Class III. All of them were in sinus rhythm except two (5%) who had atrial fibrillation. Thirty four patients (89.5%) were in second trimester of pregnancy at the time of presentation and four (10.5%) were in third trimester. Echocardiographic analysis of the mitral valve showed that the mean Wilkin’s score was 7.3. Mean mitral valve area pre procedure was 0.8 cm2. Mean gradient across the valve was 18 mmHg. Ten patients (26.5%) had mild mitral regurgitation and none had more than mild mitral regurgitation. Thirty six patients had pulmonary hypertension as assessed by tricuspid regurgitation jet velocity. All of them underwent BMV with JOMIVA balloon. Post procedure mean mitral valve area was 1.7 cm2 as assessed by echocardiography. Post procedure mean gradient across the mitral valve as assessed by echocardiography was 5 mmHg. Two patients had moderate to severe mitral regurgitation after the procedure and the rest had either no mitral regurgitation or mild mitral regurgitation after the procedure. None of the patients warranted mitral valve replacement after BMV. No patients had any manifestations of systemic embolism like cerebrovascular accident or limb ischemia after the procedure. None of the patients had preterm delivery or adverse fetal outcome during index hospitalisation. Conclusion Over the wire BMV is safe and effective method during pregnancy. The results are comparable to that of Inoue technique. BMV offers a good symptomatic improvement in pregnant women presenting with symptoms of pulmonary congestion because of Rheumatic mitral stenosis. PMID:28384909

Gap junctional coupling in the vertebrate retina: variations on one theme?

PubMed

Völgyi, Béla; Kovács-Oller, Tamás; Atlasz, Tamás; Wilhelm, Márta; Gábriel, Róbert

2013-05-01

Gap junctions connect cells in the bodies of all multicellular organisms, forming either homologous or heterologous (i.e. established between identical or different cell types, respectively) cell-to-cell contacts by utilizing identical (homotypic) or different (heterotypic) connexin protein subunits. Gap junctions in the nervous system serve electrical signaling between neurons, thus they are also called electrical synapses. Such electrical synapses are particularly abundant in the vertebrate retina where they are specialized to form links between neurons as well as glial cells. In this article, we summarize recent findings on retinal cell-to-cell coupling in different vertebrates and identify general features in the light of the evergrowing body of data. In particular, we describe and discuss tracer coupling patterns, connexin proteins, junctional conductances and modulatory processes. This multispecies comparison serves to point out that most features are remarkably conserved across the vertebrate classes, including (i) the cell types connected via electrical synapses; (ii) the connexin makeup and the conductance of each cell-to-cell contact; (iii) the probable function of each gap junction in retinal circuitry; (iv) the fact that gap junctions underlie both electrical and/or tracer coupling between glial cells. These pan-vertebrate features thus demonstrate that retinal gap junctions have changed little during the over 500 million years of vertebrate evolution. Therefore, the fundamental architecture of electrically coupled retinal circuits seems as old as the retina itself, indicating that gap junctions deeply incorporated in retinal wiring from the very beginning of the eye formation of vertebrates. In addition to hard wiring provided by fast synaptic transmitter-releasing neurons and soft wiring contributed by peptidergic, aminergic and purinergic systems, electrical coupling may serve as the 'skeleton' of lateral processing, enabling important functions such as signal averaging and synchronization. 2013 Elsevier Ltd. All rights reserved.

Optimal and Local Connectivity Between Neuron and Synapse Array in the Quantum Dot/Silicon Brain

NASA Technical Reports Server (NTRS)

Duong, Tuan A.; Assad, Christopher; Thakoor, Anikumar P.

2010-01-01

This innovation is used to connect between synapse and neuron arrays using nanowire in quantum dot and metal in CMOS (complementary metal oxide semiconductor) technology to enable the density of a brain-like connection in hardware. The hardware implementation combines three technologies: 1. Quantum dot and nanowire-based compact synaptic cell (50x50 sq nm) with inherently low parasitic capacitance (hence, low dynamic power approx.l0(exp -11) watts/synapse), 2. Neuron and learning circuits implemented in 50-nm CMOS technology, to be integrated with quantum dot and nanowire synapse, and 3. 3D stacking approach to achieve the overall numbers of high density O(10(exp 12)) synapses and O(10(exp 8)) neurons in the overall system. In a 1-sq cm of quantum dot layer sitting on a 50-nm CMOS layer, innovators were able to pack a 10(exp 6)-neuron and 10(exp 10)-synapse array; however, the constraint for the connection scheme is that each neuron will receive a non-identical 10(exp 4)-synapse set, including itself, via its efficacy of the connection. This is not a fully connected system where the 100x100 synapse array only has a 100-input data bus and 100-output data bus. Due to the data bus sharing, it poses a great challenge to have a complete connected system, and its constraint within the quantum dot and silicon wafer layer. For an effective connection scheme, there are three conditions to be met: 1. Local connection. 2. The nanowire should be connected locally, not globally from which it helps to maximize the data flow by sharing the same wire space location. 3. Each synapse can have an alternate summation line if needed (this option is doable based on the simple mask creation). The 10(exp 3)x10(exp 3)-neuron array was partitioned into a 10-block, 10(exp 2)x10(exp 3)-neuron array. This building block can be completely mapped within itself (10,000 synapses to a neuron).

Diversity in immunological synapse structure

PubMed Central

Thauland, Timothy J; Parker, David C

2010-01-01

Immunological synapses (ISs) are formed at the T cell–antigen-presenting cell (APC) interface during antigen recognition, and play a central role in T-cell activation and in the delivery of effector functions. ISs were originally described as a peripheral ring of adhesion molecules surrounding a central accumulation of T-cell receptor (TCR)–peptide major histocompatibility complex (pMHC) interactions. Although the structure of these ‘classical’ ISs has been the subject of intense study, non-classical ISs have also been observed under a variety of conditions. Multifocal ISs, characterized by adhesion molecules dispersed among numerous small accumulations of TCR–pMHC, and motile ‘immunological kinapses’ have both been described. In this review, we discuss the conditions under which non-classical ISs are formed. Specifically, we explore the profound effect that the phenotypes of both T cells and APCs have on IS structure. We also comment on the role that IS structure may play in T-cell function. PMID:21039474

Gene therapy ameliorates cardiovascular disease in dogs with mucopolysaccharidosis VII.

PubMed

Sleeper, M M; Fornasari, B; Ellinwood, N M; Weil, M A; Melniczek, J; O'Malley, T M; Sammarco, C D; Xu, L; Ponder, K P; Haskins, M E

2004-08-17

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity resulting in defective catabolism of glycosaminoglycans (GAGs). Cardiac disease is a major cause of death in MPS VII because of accumulation of GAGs in cardiovascular cells. Manifestations include cardiomyopathy, mitral and aortic valve thickening, and aortic root dilation and may cause death in the early months of life or may be compatible with a fairly normal lifespan. We previously reported that neonatal administration of a retroviral vector (RV) resulted in transduction of hepatocytes, which secreted GUSB into the blood and could be taken up by cells throughout the body. The goal of this study was to evaluate the effect on cardiac disease. Six MPS VII dogs were treated intravenously with an RV-expressing canine GUSB. Echocardiographic parameters, cardiovascular lesions, and biochemical parameters of these dogs were compared with those of normal and untreated MPS VII dogs. RV-treated dogs were markedly improved compared with untreated MPS VII dogs. Most RV-treated MPS VII dogs had mild or moderate mitral regurgitation at 4 to 5 months after birth, which improved or disappeared when evaluated at 9 to 11 and at 24 months. Similarly, mitral valve thickening present early in some animals disappeared over time, whereas aortic dilation and aortic valve thickening were absent at all times. Both myocardium and aorta had significant levels of GUSB and reduction in GAGs.

The relationship between PSD-95 clustering and spine stability in vivo.

PubMed

Cane, Michele; Maco, Bohumil; Knott, Graham; Holtmaat, Anthony

2014-02-05

The appearance and disappearance of dendritic spines, accompanied by synapse formation and elimination may underlie the experience-dependent reorganization of cortical circuits. The exact temporal relationship between spine and synapse formation in vivo remains unclear, as does the extent to which synapse formation enhances the stability of newly formed spines and whether transient spines produce synapses. We used in utero electroporation of DsRedExpress- and eGFP-tagged postsynaptic density protein 95 (PSD-95) to investigate the relationship between spine and PSD stability in mouse neocortical L2/3 pyramidal cells in vivo. Similar to previous studies, spines and synapses appeared and disappeared, even in naive animals. Cytosolic spine volumes and PSD-95-eGFP levels in spines covaried over time, suggesting that the strength of many individual synapses continuously changes in the adult neocortex. The minority of newly formed spines acquired PSD-95-eGFP puncta. Spines that failed to acquire a PSD rarely survived for more than a day. Although PSD-95-eGFP accumulation was associated with increased spine lifetimes, most new spines with a PSD did not convert into persistent spines. This indicates that transient spines may serve to produce short-lived synaptic contacts. Persistent spines that were destined to disappear showed, on average, reduced PSD-95-eGFP levels well before the actual pruning event. Altogether, our data indicate that the PSD size relates to spine stability in vivo.

Cell types and synaptic organization of the medullary electromotor nucleus in a constant frequency weakly electric fish, Sternarchus albifrons.

PubMed

Tokunaga, A; Akert, K; Sandri, C; Bennett, M V

1980-08-01

The medullary electromotor nucleus (EMN) of Sternarchus albifrons was studied at the light and electron microscopic levels. The EMN consists of a dense meshwork of myelinated axons and glial elements with interposed large neurons; it is provided with an abundant supply of capillaries. Two types of essentially adrendritic nerve cells were distinguished on the basis of size: giant neurons (approx. 70 micrometers in diameter) and large neurons (approx. 30 micrometers in diameter). Their population ratio is 1:4. Only giant cells are labelled following the injection of retrograde tracer into the spinal cord; they are therefore identified with the so-called "relay cells" of other gymnotids. Tracer experiments further suggest that the descending axons of these relay cells give off collateral branches throughout the elongated spinal electromotor nucleus. In contrast, the large cells remain unlabelled and therefore lack spinal projections; they most likely correspond to "pacemaker cells." The perikaryal surface, including axon hillock and proximal part of initial segment of both types of EMN cells, is contacted by clusters of synaptic terminals and astrocytic processes. Two main varieties of synaptic terminals occur: (1) large endings and (2) ordinary end feet with standard size (S-type) and variable size (Sv-type) clear, spherical vesicles. The junction between large endings and EMN cells is characterized by the combination of gap junctions and surrounding intermediate junctions whose freeze-fracture characteristics were morphometrically analyzed. The large endings were formed by nodes of Ranvier as well as by fiber terminations, and synchronization within the EMN may be achieved by presynaptic fibers. Some of the contacts occur directly on the initial segment, which could allow activity to bypass the soma. It is concluded that the elctromotor system of Sternarchus is comprised of a rapid conduction pathway where medullary pacemaker and relay cells as well as spinal electromotor neurons are coupled by synapses with gap junctions. In contrast to the spinal electromotor neurons, the medullary EMN cells receive synapses with morphological characteristics of chemical transmission, and the S-type and SV-type terminals may possibly correspond to Gray's Type I and Type II synapses, respectively. These synapses may be involved in modulation of the electric organ discharge frequency.

Glutamatergic synapses in neurodevelopmental disorders.

PubMed

Moretto, Edoardo; Murru, Luca; Martano, Giuseppe; Sassone, Jenny; Passafaro, Maria

2018-06-08

Neurodevelopmental disorders (NDDs) are a group of diseases whose symptoms arise during childhood or adolescence and that impact several higher cognitive functions such as learning, sociability and mood. Accruing evidence suggests that a shared pathogenic mechanism underlying these diseases is the dysfunction of glutamatergic synapses. We summarize present knowledge on autism spectrum disorders (ASD), intellectual disability (ID), Down syndrome (DS), Rett syndrome (RS) and attention-deficit hyperactivity disorder (ADHD), highlighting the involvement of glutamatergic synapses and receptors in these disorders. The most commonly shared defects involve α-amino-3-hydroxy-5-methyl- 4-isoxazole propionic acid receptors (AMPARs), N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), whose functions are strongly linked to synaptic plasticity, affecting both cell-autonomous features as well as circuit formation. Moreover, the major scaffolding proteins and, thus, the general structure of the synapse are often deregulated in neurodevelopmental disorders, which is not surprising considering their crucial role in the regulation of glutamate receptor positioning and functioning. This convergence of defects supports the definition of neurodevelopmental disorders as a continuum of pathological manifestations, suggesting that glutamatergic synapses could be a therapeutic target to ameliorate patient symptomatology. Copyright © 2017. Published by Elsevier Inc.

High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus.

PubMed

Baude, A; Nusser, Z; Molnár, E; McIlhinney, R A; Somogyi, P

1995-12-01

The cellular and subcellular localization of the GluRA, GluRB/C and GluRD subunits of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type glutamate receptor was determined in the rat hippocampus using polyclonal antipeptide antibodies in immunoperoxidase and immunogold procedures. For the localization of the GluRD subunit a new polyclonal antiserum was developed using the C-terminal sequence of the protein (residues 869-881), conjugated to carrier protein and absorbed to colloidal gold for immunization. The purified antibodies immunoprecipitated about 25% of 3[H]AMPA binding activity from the hippocampus, cerebellum or whole brain, but very little from neocortex. These antibodies did not precipitate a significant amount of 3[H]kainate binding activity. The antibodies also recognize the GluRD subunit, but not the other AMPA receptor subunits, when expressed in transfected COS-7 cells and only when permeabilized with detergent, indicating an intracellular epitope. All subunits were enriched in the neuropil of the dendritic layers of the hippocampus and in the molecular layer of the dentate gyrus. The cellular distribution of the GluRD subunit was studied more extensively. The strata radiatum, oriens and the dentate molecular layer were more strongly immunoreactive than the stratum lacunosum moleculare, the stratum lucidum and the hilus. However, in the stratum lucidum of the CA3 area and in the hilus the weakly reacting dendrites were surrounded by immunopositive rosettes, shown in subsequent electron microscopic studies to correspond to complex dendritic spines. In the stratum radiatum, the weakly reacting apical dendrites contrasted with the surrounding intensely stained neuropil. The cell bodies of pyramidal and granule cells were moderately reactive. Some non-principal cells and their dendrites in the pyramidal cell layer and in the alveus also reacted very strongly for the GluRD subunit. At the subcellular level, silver intensified immunogold particles for the GluRA, GluRB/C and GluRD subunits were present at type 1 synaptic membrane specializations on dendritic spines of pyramidal cells throughout all layers of the CA1 and CA3 areas. The most densely labelled synapses tended to be on the largest spines and many smaller spines remained unlabelled. Immunoparticle density at type 1 synapses on dendritic shafts of some non-principal cells was consistently higher than at labelled synapses of dendritic spines of pyramidal cells. Synapses established between dendritic spines and mossy fibre terminals, were immunoreactive for all studied subunits in stratum lucidum of the CA3 area. The postembedding immunogold method revealed that the AMPA type receptors are concentrated within the main body of the anatomically defined type 1 (asymmetrical) synaptic junction. Often only a part of the membrane specialization showed clustered immunoparticles. There was a sharp decrease in immunoreactive receptor density at the edge of the synaptic specialization. Immunolabelling was consistently demonstrated at extrasynaptic sites on dendrites, dendritic spines and somata. The results demonstrate that the GluRA, B/C and D subunits of the AMPA type glutamate receptor are present in many of the glutamatergic synapses formed by the entorhinal, CA3 pyramidal and mossy fibre terminals. Some interneurons have a higher density of AMPA type receptors in their asymmetrical afferent synapses than pyramidal cells. This may contribute to a lower activation threshold of interneurons as compared to principal cells by the same afferents in the hippocampal formation.

Transcatheter direct mitral valve annuloplasty with the Cardioband system for the treatment of functional mitral regurgitation.

PubMed

Taramasso, Maurizio; Inderbitzin, Devdas T; Guidotti, Andrea; Nietlispach, Fabian; Gaemperli, Oliver; Zuber, Michel; Maisano, Francesco

2016-01-01

Direct mitral valve annuloplasty is a transcatheter mitral valve repair approach that mimics the conventional surgical approach to treat functional mitral regurgitation. The Cardioband system (Valtech Cardio, Inc., Or-Yehuda, Israel) is delivered by a trans-septal approach and the implant is performed on the atrial side of the mitral annulus, under live echo and fluoroscopic guidance using multiple anchor elements. The Cardioband system obtained CE mark approval in October 2015, and initial clinical experiences are promising with regard to feasibility, safety and efficacy. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Severe mitral stenosis with atypical presentation: hemorrhagic pleural effusion--a case report and literature review.

PubMed

Albalbissi, Kais A; Burress, Jonathan W; Garcia, Israel D; Iskandar, Said B

2009-02-01

Mitral stenosis is a well-described valvular heart disease. We report a 68-year-old patient with an unusual presentation of mitral stenosis. He presented with recurrent episodes of hemorrhagic pleural effusion. Afterwards, an extensive atrial thrombosis complicated his course of illness. We will discuss how the clinical presentation of mitral stenosis is mainly dictated by the underlying pathophysiology of the disease. Also, the need for anticoagulation in the setting of mitral stenosis is often linked to the presence of atrial fibrillation. We will discuss the independent risk factors for thromboembolism in the setting of mitral stenosis. Finally, a review of the current recommendation for anticoagulation is conferred.

Mitral repair and the robot: a revolutionary tool or marketing ploy?

PubMed

Ghoneim, Aly; Bouhout, Ismail; Makhdom, Fahd; Chu, Michael W A

2018-03-01

In this review, we discuss the current evidence supporting each minimally invasive mitral repair approach and their associated controversies. Current evidence demonstrates that minimally invasive mitral repair techniques yield similar mitral repair results to conventional sternotomy with the benefits of shorter hospital stay, quicker recovery, better cosmesis and improved patient satisfaction. Despite this, broad adoption of minimally invasive mitral repair is still not achieved. Two main approaches of minimally invasive mitral repair exist: endoscopic mini-thoracotomy and robotic-assisted approaches. Both minimally invasive approaches share many commonalities; however, most centres are strongly polarized to one approach over another creating controversy and debate about the most effective minimally invasive approach.

Transaortic Alfieri Edge-to-Edge Repair for Functional Mitral Regurgitation.

PubMed

Imasaka, Ken-Ichi; Tayama, Eiki; Morita, Shigeki; Toriya, Ryohei; Tomita, Yukihiro

2018-03-01

There is controversy about handling functional mitral regurgitation in patients undergoing aortic valve or proximal aortic operations. We describe a transaortic Alfieri edge-to-edge repair for functional mitral regurgitation that reduces operative excessive invasion and prolonged cardiopulmonary bypass time. Between May 2013 and December 2016, 10 patients underwent transaortic Alfieri edge-to-edge mitral repair. There were no operative deaths. The severity of mitral regurgitation immediately after the operation by transesophageal echocardiography was none or trivial in all patients. A transaortic Alfieri edge-to-edge repair for functional mitral regurgitation is a simple and safe approach. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Complex inhibitory microcircuitry regulates retinal signaling near visual threshold

PubMed Central

Grimes, William N.; Zhang, Jun; Tian, Hua; Graydon, Cole W.; Hoon, Mrinalini; Rieke, Fred

2015-01-01

Neuronal microcircuits, small, localized signaling motifs involving two or more neurons, underlie signal processing and computation in the brain. Compartmentalized signaling within a neuron may enable it to participate in multiple, independent microcircuits. Each A17 amacrine cell in the mammalian retina contains within its dendrites hundreds of synaptic feedback microcircuits that operate independently to modulate feedforward signaling in the inner retina. Each of these microcircuits comprises a small (<1 μm) synaptic varicosity that typically receives one excitatory synapse from a presynaptic rod bipolar cell (RBC) and returns two reciprocal inhibitory synapses back onto the same RBC terminal. Feedback inhibition from the A17 sculpts the feedforward signal from the RBC to the AII, a critical component of the circuitry mediating night vision. Here, we show that the two inhibitory synapses from the A17 to the RBC express kinetically distinct populations of GABA receptors: rapidly activating GABAARs are enriched at one synapse while more slowly activating GABACRs are enriched at the other. Anatomical and electrophysiological data suggest that macromolecular complexes of voltage-gated (Cav) channels and Ca2+-activated K+ channels help to regulate GABA release from A17 varicosities and limit GABACR activation under certain conditions. Finally, we find that selective elimination of A17-mediated feedback inhibition reduces the signal to noise ratio of responses to dim flashes recorded in the feedforward pathway (i.e., the AII amacrine cell). We conclude that A17-mediated feedback inhibition improves the signal to noise ratio of RBC-AII transmission near visual threshold, thereby improving visual sensitivity at night. PMID:25972578

Spiking Neural Classifier with Lumped Dendritic Nonlinearity and Binary Synapses: A Current Mode VLSI Implementation and Analysis.

PubMed

Bhaduri, Aritra; Banerjee, Amitava; Roy, Subhrajit; Kar, Sougata; Basu, Arindam

2018-03-01

We present a neuromorphic current mode implementation of a spiking neural classifier with lumped square law dendritic nonlinearity. It has been shown previously in software simulations that such a system with binary synapses can be trained with structural plasticity algorithms to achieve comparable classification accuracy with fewer synaptic resources than conventional algorithms. We show that even in real analog systems with manufacturing imperfections (CV of 23.5% and 14.4% for dendritic branch gains and leaks respectively), this network is able to produce comparable results with fewer synaptic resources. The chip fabricated in [Formula: see text]m complementary metal oxide semiconductor has eight dendrites per cell and uses two opposing cells per class to cancel common-mode inputs. The chip can operate down to a [Formula: see text] V and dissipates 19 nW of static power per neuronal cell and [Formula: see text] 125 pJ/spike. For two-class classification problems of high-dimensional rate encoded binary patterns, the hardware achieves comparable performance as software implementation of the same with only about a 0.5% reduction in accuracy. On two UCI data sets, the IC integrated circuit has classification accuracy comparable to standard machine learners like support vector machines and extreme learning machines while using two to five times binary synapses. We also show that the system can operate on mean rate encoded spike patterns, as well as short bursts of spikes. To the best of our knowledge, this is the first attempt in hardware to perform classification exploiting dendritic properties and binary synapses.

Glia-derived signals induce synapse formation in neurones of the rat central nervous system

PubMed Central

Nägler, Karl; Mauch, Daniela H; Pfrieger, Frank W

2001-01-01

To study the effects of glial cells on synapse formation, we established microcultures of purified rat retinal ganglion cells (RGCs) and monitored synapse (autapse) development in single neurones using electrophysiological recordings, FM1-43 labelling and immunocytochemistry.Solitary neurones grew ramifying neurites, but formed only very few and inefficient excitatory autapses, when cultured for up to 2 weeks in defined medium and in the absence of glial cells.Treatment of glia-free microcultures of RGCs with glia-conditioned medium (GCM) increased the number of autapses per neurone by up to 10-fold. This was indicated by a similar increase in the frequency of spontaneous events and the number of FM1-43-labelled functional release sites and of puncta, where pre- and postsynaptic markers colocalized.In addition, GCM treatment enhanced the efficacy of presynaptic transmitter release as indicated by lower failure rates of stimulation-induced excitatory autaptic currents, a 200-fold increase in the frequency of asynchronous release and an accelerated stimulation-induced FM1-43 destaining. Furthermore, GCM induced an increase in the quantal size.GCM affected autaptic activity not immediately, but with a delay of 24 h, and the effects on stimulation-induced autaptic currents occurred before changes in the frequency of spontaneous events indicating an early strengthening of existing autapses followed by a later increase in autapse number.The observed effects were mediated by proteinase K-sensitive factors in GCM and occurred independently of electrical activity.These results suggest that soluble glia-derived signals induce synapse formation and maturation in neurones of the central nervous system (CNS). PMID:11410625

Towards an atrio-ventricular delay optimization assessed by a computer model for cardiac resynchronization therapy

NASA Astrophysics Data System (ADS)

Ojeda, David; Le Rolle, Virginie; Tse Ve Koon, Kevin; Thebault, Christophe; Donal, Erwan; Hernández, Alfredo I.

2013-11-01

In this paper, lumped-parameter models of the cardiovascular system, the cardiac electrical conduction system and a pacemaker are coupled to generate mitral ow pro les for di erent atrio-ventricular delay (AVD) con gurations, in the context of cardiac resynchronization therapy (CRT). First, we perform a local sensitivity analysis of left ventricular and left atrial parameters on mitral ow characteristics, namely E and A wave amplitude, mitral ow duration, and mitral ow time integral. Additionally, a global sensitivity analysis over all model parameters is presented to screen for the most relevant parameters that a ect the same mitral ow characteristics. Results provide insight on the in uence of left ventricle and atrium in uence on mitral ow pro les. This information will be useful for future parameter estimation of the model that could reproduce the mitral ow pro les and cardiovascular hemodynamics of patients undergoing AVD optimization during CRT.

Mitral stenosis due to pannus overgrowth after rigid ring annuloplasty.

PubMed

Oda, Takeshi; Kato, Seiya; Tayama, Eiki; Fukunaga, Shuji; Akashi, Hidetoshi; Aoyagi, Shigeaki

2010-03-01

Although mitral stenosis (MS) due to pannus overgrowth after mitral valve repair for rheumatic mitral regurgitation (MR) is not uncommon, it is extremely rare in relation to non-rheumatic mitral regurgitation. Whilst it has been suggested that the rigid annuloplasty ring induces pannus overgrowth in the same manner as the flexible ring, to date only in cases using the flexible ring has pannus formation been confirmed by a pathological examination after redo surgery. The case is described of a woman who had undergone mitral valve repair using a 28 mm rigid ring three years previously because of non-rheumatic MR, and subsequently suffered from MS due to pannus formation over the annuloplasty ring. To the present authors' knowledge, this is the first report of MS due to pannus formation after mitral valve repair using a rigid annuloplasty ring to treat non-rheumatic MR documented at reoperation.

Tubulin and Actin Interplay at the T Cell and Antigen-Presenting Cell Interface

PubMed Central

Martín-Cófreces, Noa Beatriz; Alarcón, Balbino; Sánchez-Madrid, Francisco

2011-01-01

T cells reorganize their actin and tubulin-based cytoskeletons to provide a physical basis to the immune synapse. However, growing evidence shows that their roles on T cell activation are more dynamic than merely serving as tracks or scaffold for different molecules. The crosstalk between both skeletons may be important for the formation and movement of the lamella at the immunological synapse by increasing the adhesion of the T cell to the antigen-presenting cells (APC), thus favoring the transport of components toward the plasma membrane and in turn regulating the T-APC intercellular communication. Microtubules and F-actin appear to be essential for the transport of the different signaling microclusters along the membrane, therefore facilitating the propagation of the signal. Finally, they can also be important for regulating the endocytosis, recycling, and degradation of the T cell receptor signaling machinery, thus helping both to sustain the activated state and to switch it off. PMID:22566814

Percutaneous transvenous mitral commissurotomy in patients with mitral stenosis and coexistent hyperthyroidism.

PubMed

Wang, P W; Hung, J S; Fu, M; Yeh, K H; Wu, J J

1996-01-01

Percutaneous transvenous mitral commissurotomy (PTMC) was performed successfully without complications in 3 patients with severe mitral stenosis and hyperthyroidism. All 3 patients had pliable, noncalcified mitral valves. One patient who had been treated with methimazole for 6 months was still in a hyperthyroid state when she presented with intractable congestive heart failure and was found to have severe mitral stenosis. The heart failure improved immediately after PTMC, but the patient remained in New York Heart Association functional class 2 until a euthyroid state was achieved with I131 therapy. In the other 2 patients, hyperthyroidism was unsuspected at the time of PTMC. Unexpectedly suboptimal symptom improvement led to the diagnosis of hyperthyroidism 1 month after the intervention. In all 3 patients, PTMC resulted in an immediate hemodynamic and clinical improvement. However, complete clinical improvement occurred only when euthyroid state was achieved after antithyroid treatment. The present study suggests that PTMC is a safe and effective intervention modality in patients with coexisting hyperthyroidism and severe mitral stenosis. The procedure may be considered a therapeutic option in patients with hyperthyroidism and severe mitral stenosis.

A Dynamic Analysis of Secretory Granules Containing Proteins Involved In Learning

NASA Astrophysics Data System (ADS)

Prahl, Louis; Simon, Alex; Jacobs, Conor; Fulwiler, Audrey; Hilken, Lindsay; Scalettar, Bethe; Lochner, Janis

2010-10-01

Formation and encoding of long-term memories requires a series of structural changes at synapses, or sites of neuronal communication, in the hippocampus; these changes are mediated by neuromodulatory proteins and serve to strengthen synapses to improve communication. Two prominent neuromodulators, tissue plasminogen activator (tPA) and brain-derived neurotrophic factor (BDNF), are copackaged into secretory granules (SGs) in the body of nerve cells and are transported to distal synapses by motor proteins. At synapses, particularly presynaptic sites, the fate of tPA and BDNF is largely unknown. Motivated by this, and by recent data implicating presynaptic BDNF in early phases of learning, we used fluorescence microscopy to elucidate dynamic properties of presynaptic tPA and BDNF. We find that presynaptic SGs containing tPA and/or BDNF undergo Brownian and anomalous diffusive motion that, in 75% of cases, is so slow that it typically would be classified as immobility. These results suggest that tPA and BDNF are retained at presynaptic sites to facilitate their corelease and role in learning.

Subunit-dependent postsynaptic expression of kainate receptors on hippocampal interneurons in area CA1

PubMed Central

Wondolowski, Joyce; Frerking, Matthew

2009-01-01

Kainate receptors (KARs) contribute to postsynaptic excitation in only a select subset of neurons. To define the parameters that specify the postsynaptic expression of KARs, we examined the contribution of KARs to EPSCs on hippocampal interneurons in area CA1. Interneurons in stratum radiatum/lacunosum-moleculare (SR/SLM) express KARs both with and without the GluR5 subunit, but KAR-mediated EPSCs are generated mainly, if not entirely, by GluR5-containing KARs. Extrasynaptic glutamate spillover profoundly recruits AMPARs with little effect on KARs, indicating that KARs are targeted at the synapse more precisely than AMPARs. However, spontaneous EPSCs with a conventional AMPAR component did not have a resolvable contribution of KARs, suggesting that the KARs that contribute to the evoked EPSCs are at a distinct set of synapses. GluR5-containing KARs on interneurons in stratum oriens do not contribute substantially to the EPSC. We conclude that KARs are localized to synapses by cell type-, synapse-, and subunit-selective mechanisms. PMID:19144856

Retrograde Signaling from Progranulin to Sort1 Counteracts Synapse Elimination in the Developing Cerebellum.

PubMed

Uesaka, Naofumi; Abe, Manabu; Konno, Kohtarou; Yamazaki, Maya; Sakoori, Kazuto; Watanabe, Takaki; Kao, Tzu-Huei; Mikuni, Takayasu; Watanabe, Masahiko; Sakimura, Kenji; Kano, Masanobu

2018-02-21

Elimination of redundant synapses formed early in development and strengthening of necessary connections are crucial for shaping functional neural circuits. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs) with similar strengths. A single CF is strengthened whereas the other CFs are eliminated in each PC during postnatal development. The underlying mechanisms, particularly for the strengthening of single CFs, are poorly understood. Here we report that progranulin, a multi-functional growth factor implicated in the pathogenesis of frontotemporal dementia, strengthens developing CF synaptic inputs and counteracts their elimination from postnatal day 11 to 16. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination. We propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single "winner" CFs that survive synapse elimination. Copyright © 2018 Elsevier Inc. All rights reserved.

Dendritic position is a major determinant of presynaptic strength

PubMed Central

de Jong, Arthur P.H.; Schmitz, Sabine K.; Toonen, Ruud F.G.

2012-01-01

Different regulatory principles influence synaptic coupling between neurons, including positional principles. In dendrites of pyramidal neurons, postsynaptic sensitivity depends on synapse location, with distal synapses having the highest gain. In this paper, we investigate whether similar rules exist for presynaptic terminals in mixed networks of pyramidal and dentate gyrus (DG) neurons. Unexpectedly, distal synapses had the lowest staining intensities for vesicular proteins vGlut, vGAT, Synaptotagmin, and VAMP and for many nonvesicular proteins, including Bassoon, Munc18, and Syntaxin. Concomitantly, distal synapses displayed less vesicle release upon stimulation. This dependence of presynaptic strength on dendritic position persisted after chronically blocking action potential firing and postsynaptic receptors but was markedly reduced on DG dendrites compared with pyramidal dendrites. These data reveal a novel rule, independent of neuronal activity, which regulates presynaptic strength according to dendritic position, with the strongest terminals closest to the soma. This gradient is opposite to postsynaptic gradients observed in pyramidal dendrites, and different cell types apply this rule to a different extent. PMID:22492722

A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification.

PubMed

Ponasenko, Anastasia V; Khutornaya, Maria V; Kutikhin, Anton G; Rutkovskaya, Natalia V; Tsepokina, Anna V; Kondyukova, Natalia V; Yuzhalin, Arseniy E; Barbarash, Leonid S

2016-08-31

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification.

A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification

PubMed Central

Ponasenko, Anastasia V.; Khutornaya, Maria V.; Kutikhin, Anton G.; Rutkovskaya, Natalia V.; Tsepokina, Anna V.; Kondyukova, Natalia V.; Yuzhalin, Arseniy E.; Barbarash, Leonid S.

2016-01-01

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification. PMID:27589735

Long-term Results After Open Mitral Commissurotomy for a One-Month-Old Infant With Mitral Stenosis.

PubMed

Kitaichi, Takashi; Sugano, Mikio; Arase, Hiroki; Kawatani, Yohei; Kameta, Kanako; Kurobe, Hirotsugu; Fujimoto, Eiki; Ono, Akemi; Hayabuchi, Yasunobu; Fujita, Hiroshi; Sogabe, Hitoshi; Kitagawa, Tetsuya

2017-01-01

The strategy for an infant with congenital mitral stenosis should be determined by three important factors: left ventricular volume, the degree of the systemic outflow tract obstruction, and the type of mitral valve dysfunction. A successful staged biventricular repair in early infancy for a patient who had congenital mitral stenosis with short chordae, hypoplastic left ventricle and coarctation of the aorta, and the long-term results are described. There were the following important hemodynamic factors that led to the successful biventricular repair in the patient. Total systemic output was barely supplied through the hypoplastic left ventricle after closure of the ductus arteriosus on admission. The neonate underwent repair of coarctation of the aorta alone as the initial stage at 9 days after birth. Also, spontaneous closure of the foramen ovale following repair of coarctation of the aorta accelerated the progressive left ventricular growth. Open mitral commissurotomy with an interatrial fenestration using the modified Brawley's approach was performed for a 40-day-old infant. Good left ventricular growth and good mitral valve function have been observed for 18 years after open mitral commissurotomy. Appropriate early augmentation of left ventricular inflow through the mitral valve might be effective for growth of a hypoplastic left ventricle. J. Med. Invest. 64: 187-191, February, 2017.

Percutaneous Transvenous Mitral Annuloplasty (PTMA) with the Viking device reduces pacing-induced mitral regurgitation.

PubMed

Kimblad, Per Ola; Harnek, Jan; Roijer, Anders; Meurling, Carl; Brandt, Johan; Solem, Jan Otto

2005-11-01

The new percutaneous mitral annuloplasty Viking device was evaluated in surviving sheep with pacing-induced mitral regurgitation. Twenty sheep were subjected to rapid ventricular pacing for one to three months, leading to cardiomyopathy and mitral regurgitation. Device implantation could be successfully performed in 11 of these animals after pacemaker treatment for 64+/-7 days. The device-related procedure time was 12+/-2 min. The mean follow-up time was 58+/-8 days after implantation of the device. Mitral annulus septo-lateral diameter was significantly reduced after insertion of the device, from 35+/-1 mm before implantation to 30+/-1 mm at the final follow up intracardiac echocardiography (P = 0.0097). The degree of mitral regurgitation (on a scale from 0 to 4) was 2.6+/-0.2 before device implantation and decreased to 0.8+/-0.2 after treatment (P = 0.0039), and the vena contracta was reduced from 7+/-0.4 mm to 3+/-0.8 mm (P = 0.0019). Angiography showed no signs of impairment of the coronary arteries. No thrombosis was observed. These results indicate that the septo-lateral diameter of the mitral annulus, and the degree of experimentally induced mitral regurgitation, can be significantly reduced with a percutaneous catheter technique in surviving sheep.

A Study on Cerebral Embolism in Mitral Stenosis

PubMed Central

Kwon, Osun; Kim, Myung Hwan; Kim, Kwon Sam; Bae, Jong Hoa; Kim, Myung Shick; Song, Jung Sang

1986-01-01

To evaluate the significance of episodes of cerebral embolism in patients with mitral valve disease in Korea, 128 patients with echocardiographic diagnosis of mitral valve disease were examined. Among these, 82 patients had predominant mitral stenosis. The clinical features of 82 patients with mitral stenosis have been reviewed to elucidate the factors favoring cerebral embolism which occurred in 19 patients, i.e., incidence of 23.2%.Atrial fibrillation was present in 16 of 19 patients with cerebral embolism (84.2%). Cerebral embolic episodes occurred in 16 of 47 patients with atrial fibrillation (34.0%).The mean age (55.3 ± 12.1 years) of patients without cerebral embolism was significantly older than that (43.2 ± 14.6 years) of patients without cerebral embolism (P<0.005).There was no significant relationship between the incidence of embolism and sex, left atrial thrombi, left atrium/aortic root diameter, mitral valvular orifice area, mitral valvular vegetation or calcification, left ventricular enddiastolic dimension or left ventricular posterior wall thickness. Cerebral embolism is common in patients with mitral stenosis in our country. The presence of atrial fibrillation and low cardiac output increase the attack of cerebral emboli whereas the severity of mitral stenosis, as judged by valve area, may not correlate with the occurrence of emboli. The best treatment for cerebral embolism is prevention. Therefore, we believe that more vigorous treatment of patients with mitral valve disease who are old or associated with atrial fibrillation as well as previous embolic history is indicated. PMID:15759378

Echocardiographic versus histologic findings in Marfan syndrome.

PubMed

Gu, Xiaoyan; He, Yihua; Li, Zhian; Han, Jiancheng; Chen, Jian; Nixon, J V Ian

2015-02-01

This retrospective study attempted to establish the prevalence of multiple-valve involvement in Marfan syndrome and to compare echocardiographic with histopathologic findings in Marfan patients undergoing valvular or aortic surgery. We reviewed echocardiograms of 73 Marfan patients who underwent cardiovascular surgery from January 2004 through October 2009. Tissue histology was available for comparison in 29 patients. Among the 73 patients, 66 underwent aortic valve replacement or the Bentall procedure. Histologic findings were available in 29 patients, all of whom had myxomatous degeneration. Of 63 patients with moderate or severe aortic regurgitation as determined by echocardiography, 4 had thickened aortic valves. The echocardiographic findings in 18 patients with mitral involvement included mitral prolapse in 15. Of 11 patients with moderate or severe mitral regurgitation as determined by echocardiography, 4 underwent mitral valve repair and 7 mitral valve replacement. Histologic findings among mitral valve replacement patients showed thickened valve tissue and myxomatous degeneration. Tricuspid involvement was seen echocardiographically in 8 patients, all of whom had tricuspid prolapse. Two patients had severe tricuspid regurgitation, and both underwent repair. Both mitral and tricuspid involvement were seen echocardiographically in 7 patients. Among the 73 patients undergoing cardiac surgery for Marfan syndrome, 66 had moderate or severe aortic regurgitation, although their valves manifested few histologic changes. Eighteen patients had mitral involvement (moderate or severe mitral regurgitation, prolapse, or both), and 8 had tricuspid involvement. Mitral valves were most frequently found to have histologic changes, but the tricuspid valve was invariably involved.

Modulation of the tissue reninangiotensin-aldosterone system in dogs with chronic mild regurgitation through the mitral valve.

PubMed

Fujii, Yoko; Orito, Kensuke; Muto, Makoto; Wakao, Yoshito

2007-10-01

To investigate whether the tissue and plasma renin-angiotensin-aldosterone system (RAAS) is activated in dogs with mild regurgitation through the mitral valve and determine the contribution of chymase and angiotensin-converting enzyme (ACE) to the activation of the RAAS and potential production of angiotensin II during the chronic stage of mild mitral valve regurgitation. 5 Beagles with experimentally induced mild mitral valve regurgitation and 6 clinically normal (control) Beagles. Tissue ACE and chymase-like activities and plasma RAAS were measured and the RAAS evaluated approximately 1,000 days after experimental induction of mitral valve regurgitation in the 5 dogs. Dogs with experimentally induced mitral valve regurgitation did not have clinical signs of the condition, although echocardiography revealed substantial eccentric hyper- trophy. On the basis of these findings, dogs with mitral valve regurgitation were classified as International Small Animal Cardiac Health Council class Ib. Plasma activity of renin and plasma concentrations of angiotensin I, angiotensin II, and aldosterone were not significantly different between dogs with mitral valve regurgitation and clinically normal dogs. Tissue ACE activity was significantly increased and chymase-like activity significantly decreased in dogs with mitral valve regurgitation, compared with values in clinically normal dogs. The tissue RAAS was modulated without changes in the plasma RAAS in dogs with mild mitral valve regurgitation during the chronic stage of the condition. An ACE-dependent pathway may be a major route for production of angiotensin II during this stage of the condition.

Assessment of insulin-like growth factor-1 (IGF-I) level in patients with rheumatic mitral stenosis.

PubMed

Deveci, Onur S; Yavuz, Bunyamin; Sen, Omer; Deniz, Ali; Ozkan, Selcuk; Dal, Kursat; Ata, Naim; Baser, Salih; Akin, Kadir O; Kucukazman, Metin; Beyan, Esin; Ertugrul, Derun T

2015-03-01

Insulin-like growth factor-1 may serve some regulatory function in the immune system. Rheumatic mitral stenosis is related to autoimmune heart valve damage after streptococcal infection. The aim of this study was to assess the level of insulin-like growth factor-1 and its correlation with the Wilkins score in patients with rheumatic mitral stenosis. A total of 65 patients with rheumatic mitral stenosis and 62 age- and sex-matched control subjects were enrolled in this study. All subjects underwent transthoracic echocardiography. The mitral valve area and Wilkins score were evaluated for all patients. Biochemical parameters and serum insulin-like growth factor-1 levels were measured. Demographic data were similar in the rheumatic mitral stenosis and control groups. The mean mitral valve area was 1.6±0.4 cm2 in the rheumatic mitral stenosis group. The level of insulin-like growth factor-1 was significantly higher in the rheumatic mitral stenosis group than in the control group (104 (55.6-267) versus 79.1 (23.0-244.0) ng/ml; p=0.039). There was a significant moderate positive correlation between insulin-like growth factor-1 and thickening of leaflets score of Wilkins (r=0.541, p<0.001). The present study demonstrated that serum insulin-like growth factor-1 levels were significantly higher in the rheumatic mitral stenosis group compared with control subjects and that insulin-like growth factor-1 level was also correlated with the Wilkins score. It can be suggested that there may be a link between insulin-like growth factor-1 level and immune pathogenesis of rheumatic mitral stenosis.

Effect of balloon mitral valvotomy on left ventricular function in rheumatic mitral stenosis.

PubMed

Rajesh, Gopalan Nair; Sreekumar, Pradeep; Haridasan, Vellani; Sajeev, C G; Bastian, Cicy; Vinayakumar, D; Kadermuneer, P; Mathew, Dolly; George, Biju; Krishnan, M N

Mitral stenosis (MS) is found to produce left ventricular (LV) dysfunction in some studies. We sought to study the left ventricular function in patients with rheumatic MS undergoing balloon mitral valvotomy (BMV). Ours is the first study to analyze effect of BMV on mitral annular plane systolic excursion (MAPSE), and to quantify prevalence of longitudinal left ventricular dysfunction in rheumatic MS. In this prospective cohort study, we included 43 patients with severe rheumatic mitral stenosis undergoing BMV. They were compared to twenty controls whose distribution of age and gender were similar to that of patients. The parameters compared were LV ejection fraction (EF) by modified Simpson's method, mitral annular systolic velocity (MASV), MAPSE, mitral annular early diastolic velocity (E'), and myocardial performance index (MPI). These parameters were reassessed immediately following BMV and after 3 months of procedure. MASV, MAPSE, E', and EF were significantly lower and MPI was higher in mitral stenosis group compared to controls. Impaired longitudinal LV function was present in 77% of study group. MAPSE and EF did not show significant change after BMV while MPI, MASV, and E' improved significantly. MASV and E' showed improvement immediately after BMV, while MPI decreased only at 3 months follow-up. There were significantly lower mitral annular motion parameters including MAPSE in patients with rheumatic mitral stenosis. Those with atrial fibrillation had higher MPI. Immediately after BMV, there was improvement in LV long axis function with a gradual improvement in global LV function. There was no significant change of MAPSE after BMV. Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

Long-Term Results of Mitral Valve Repair

PubMed Central

da Costa, Francisco Diniz Affonso; Colatusso, Daniele de Fátima Fornazari; Martin, Gustavo Luis do Santos; Parra, Kallyne Carolina Silva; Botta, Mariana Cozer; Balbi Filho, Eduardo Mendel; Veloso, Myrian; Miotto, Gabriela; Ferreira, Andreia Dumsch de Aragon; Colatusso, Claudinei

2018-01-01

Introduction Current guidelines state that patients with severe mitral regurgitation should be treated in reference centers with a high reparability rate, low mortality rate, and durable results. Objective To analyze our global experience with the treatment of organic mitral regurgitation from various etiologies operated in a single center. Methods We evaluated all surgically treated patients with organic mitral regurgitation from 2004-2017. Patients were evaluated clinically and by echocardiography every year. We determined early and late survival rates, valve related events and freedom from recurrent mitral regurgitation and tricuspid regurgitation. Valve failure was defined as any mitral regurgitation ≥ moderate degree or the need for reoperation for any reason. Results Out of 133 patients with organic mitral regurgitation, 125 (93.9%) were submitted to valve repair. Mean age was 57±15 years and 52 patients were males. The most common etiologies were degenerative disease (73 patients) and rheumatic disease (34 patients). Early mortality was 2.4% and late survival was 84.3% at 10 years, which are similar to the age- and gender-matched general population. Only two patients developed severe mitral regurgitation, and both were reoperated (95.6% at 10 years). Freedom from mitral valve failure was 84.5% at 10 years, with no difference between degenerative and rheumatic valves. Overall, late ≥ moderate tricuspid regurgitation was present in 34% of the patients, being more common in the rheumatic ones. The use of tricuspid annuloplasty abolished this complication. Conclusion We have demonstrated that mitral regurgitation due to organic mitral valve disease from various etiologies can be surgically treated with a high repair rate, low early mortality and long-term survival that are comparable to the matched general population. Concomitant treatment of atrial fibrillation and tricuspid valve may be important adjuncts to optimize long-term results. PMID:29617498

Implantation of personalized, biocompatible mitral annuloplasty rings: feasibility study in an animal model

PubMed Central

Sündermann, Simon H.; Gessat, Michael; Cesarovic, Nikola; Frauenfelder, Thomas; Biaggi, Patric; Bettex, Dominique; Falk, Volkmar; Jacobs, Stephan

2013-01-01

OBJECTIVES Implantation of an annuloplasty ring is an essential component of a durable mitral valve repair. Currently available off-the-shelf rings still do not cover all the variations in mitral annulus anatomy and pathology from subject to subject. Computed tomography (CT) and echo imaging allow for 3-D segmentation of the mitral valve and mitral annulus. The concept of tailored annuloplasty rings has been proposed although, to date, no surgically applicable implementation of patient-specific annuloplasty rings has been seen. The objective of this trial was to prove the concept of surgical implantation of a model-guided, personalized mitral annuloplasty ring, manufactured based on individual CT-scan models. METHODS ECG-gated CT angiography was performed in six healthy pigs under general anaesthesia. Based on the individual shape of the mitral annulus in systole, a customized solid ring with integrated suturing holes was designed and manufactured from a biocompatible titanium alloy by a rapid process using laser melting. The ring was implanted three days later and valve function was assessed by intraoperative echocardiography. The macroscopic annulus–annuloplasty match was assessed after heart explantation. RESULTS CT angiography provided good enough image quality in all animals to allow for segmentation of the mitral annulus. The individually tailored mitral rings were manufactured and successfully implanted in all pigs. In 50%, a perfect matching of the implanted ring and the mitral annulus was achieved. In one animal, a slight deviation of the ring shape from the circumference was seen postoperatively. The rings implanted in the first two animals were significantly oversized but the deviation did not affect valve competence. CONCLUSIONS CT image quality and accuracy of the dimensions of the mitral annulus were sufficient for digital modelling and rapid manufacturing of mitral rings. Implantation of individually tailored annuloplasty rings is feasible. PMID:23287589

Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission.

PubMed

Lalic, Tatjana; Pettingill, Philippa; Vincent, Angela; Capogna, Marco

2011-01-01

Limbic encephalitis (LE) is a central nervous system (CNS) disease characterized by subacute onset of memory loss and epileptic seizures. A well-recognized form of LE is associated with voltage-gated potassium channel complex antibodies (VGKC-Abs) in the patients' sera. We aimed to test the hypothesis that purified immunoglobulin G (IgG) from a VGKC-Ab LE serum would excite hippocampal CA3 pyramidal cells by reducing VGKC function at mossy-fiber (MF)-CA3 pyramidal cell synapses. We compared the effects of LE and healthy control IgG by whole-cell patch-clamp and extracellular recordings from CA3 pyramidal cells of rat hippocampal acute slices. We found that the LE IgG induced epileptiform activity at a population level, since synaptic stimulation elicited multiple population spikes extracellularly recorded in the CA3 area. Moreover, the LE IgG increased the rate of tonic firing and strengthened the MF-evoked synaptic responses. The synaptic failure of evoked excitatory postsynaptic currents (EPSCs) was significantly lower in the presence of the LE IgG compared to the control IgG. This suggests that the LE IgG increased the release probability on MF-CA3 pyramidal cell synapses compared to the control IgG. Interestingly, α-dendrotoxin (120 nm), a selective Kv1.1, 1.2, and 1.6 subunit antagonist of VGKC, mimicked the LE IgG-mediated effects. This is the first functional demonstration that LE IgGs reduce VGKC function at CNS synapses and increase cell excitability. Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

PubMed Central

2011-01-01

Background Memory deficits in Alzheimer's disease (AD) manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/Shank3 scaffold assembly within the PSD is Zn2+-dependent and that the amyloid beta protein (Aβ) is able to bind Zn2+, we hypothesize that sequestration of Zn2+ ions by Aβ contributes to ProSAP/Shank platform malformation. Results To test this hypothesis, we designed multiple in vitro and in vivo assays demonstrating ProSAP/Shank dysregulation in rat hippocampal cultures following Aβ oligomer accumulation. These changes were independent from alterations on ProSAP/Shank transcriptional level. However, application of soluble Aβ prevented association of Zn2+ ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn2+ clusters within dendrites. Zn2+ supplementation or saturation of Aβ with Zn2+ ions prior to cell treatment was able to counter the effects induced by Aβ on synapse density and ProSAP2/Shank3 levels at the PSD. Interestingly, intracellular Zn2+ levels in APP-PS1 mice and human AD hippocampus are reduced along with a reduction in synapse density and synaptic ProSAP2/Shank3 and Shank1 protein levels. Conclusions We conclude that sequestration of Zn2+ ions by Aβ significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature) synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons. PMID:21939532

Optogenetics to target actin-mediated synaptic loss in Alzheimer's

NASA Astrophysics Data System (ADS)

Zahedi, Atena; DeFea, Kathryn; Ethell, Iryna

2013-03-01

Numerous studies in Alzheimer's Disease (AD) animal models show that overproduction of Aβ peptides and their oligomerization can distort dendrites, damage synapses, and decrease the number of dendritic spines and synapses. Aβ may trigger synapse loss by modulating activity of actin-regulating proteins, such as Rac1 and cofilin. Indeed, Aβ1-42 oligomers can activate actin severing protein cofilin through calcineurin-mediated activation of phosphatase slingshot and inhibit an opposing pathway that suppresses cofilin phosphorylation through Rac-mediated activation of LIMK1. Excessive activation of actin-severing protein cofilin triggers the formation of a non-dynamic actin bundles, called rods that are found in AD brains and cause loss of synapses. Hence, regulation of these actin-regulating proteins in dendritic spines could potentially provide useful tools for preventing the synapse/spine loss associated with earlier stages of AD neuropathology. However, lack of spatiotemporal control over their activity is a key limitation. Recently, optogenetic advancements have provided researchers with convenient light-activating proteins such as photoactivatable Rac (PARac). Here, we transfected cultured primary hippocampal neurons and human embryonic kidney (HEK) cells with a PARac/ mCherry-containing plasmid and the mCherry-positive cells were identified and imaged using an inverted fluorescence microscope. Rac1 activation was achieved by irradiation with blue light (480nm) and live changes in dendritic spine morphology were observed using mCherry (587nm). Rac activation was confirmed by immunostaining for phosphorylated form of effector proteinP21 protein-activated kinase 1 (PAK1) and reorganization of actin. Thus, our studies confirm the feasibility of using the PA-Rac construct to trigger actin re-organization in the dendritic spines.

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors

PubMed Central

Parmelee, Caitlyn M.; Chen, Minghui; Cork, Karlene M.; Curto, Carina; Thoreson, Wallace B.

2014-01-01

At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca2+) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, τ = 1/(Dρδs), where D is the vesicle diffusion coefficient, δ is the vesicle diameter, ρ is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons. PMID:25311636

Ablation of glutamate receptor GluRδ2 in adult Purkinje cells causes multiple innervation of climbing fibers by inducing aberrant invasion to parallel fiber innervation territory.

PubMed

Miyazaki, Taisuke; Yamasaki, Miwako; Takeuchi, Tomonori; Sakimura, Kenji; Mishina, Masayoshi; Watanabe, Masahiko

2010-11-10

Glutamate receptor GluRδ2 is exclusively expressed in Purkinje cells (PCs) from early development and plays key roles in parallel fiber (PF) synapse formation, elimination of surplus climbing fibers (CFs), long-term depression, motor coordination, and motor learning. To address its role in adulthood, we previously developed a mouse model of drug-induced GluRδ2 ablation in adult PCs (Takeuchi et al., 2005). In that study, we demonstrated an essential role to maintain the connectivity of PF-PC synapses, based on the observation that both mismatching of presynaptic and postsynaptic specializations and disconnection of PF-PC synapses are progressively increased after GluRδ2 ablation. Here, we pursued its role for CF wiring in adult cerebellum. In parallel with the disconnection of PF-PC synapses, ascending CF branches exhibited distal extension to innervate distal dendrites of the target and neighboring PCs. Furthermore, transverse CF branches, a short motile collateral rarely forming synapses in wild-type animals, displayed aberrant mediolateral extension to innervate distal dendrites of neighboring and remote PCs. Consequently, many PCs were wired by single main CF and other surplus CFs innervating a small part of distal dendrites. Electrophysiological recording further revealed that surplus CF-EPSCs characterized with slow rise time and small amplitude emerged after GluRδ2 ablation, and increased progressively both in number and amplitude. Therefore, GluRδ2 is essential for maintaining CF monoinnervation in adult cerebellum by suppressing aberrant invasion of CF branches to the territory of PF innervation. Thus, GluRδ2 fuels heterosynaptic competition and gives PFs the competitive advantages over CFs throughout the animal's life.

Disc erosion in Models 103 and 104 of Beall mitral valve prostheses

PubMed Central

Gómez, Ricardo; Verduras, María José; Lopez-Quintana, Alfonso; Riera, Luis; Zerolo, Ignacio; Martinez-Bordiu, Cristóbal

1981-01-01

Three cases of severe disc variance and erosion of the Teflon-disc Beall mitral valve prosthesis (Models 103 and 104) are reported. In two patients, the Beall mitral valves were excised and replaced with two Björk-Shiley mitral valves. The remaining patient did not survive, and at autopsy, the lens was found at the aortic bifurcation level. Because of this potentially lethal complication, careful follow-up of patients with Beall mitral valve prostheses (Models 103 and 104) is recommended. Images PMID:15216211

A new cannulation method for isolated mitral valve surgery--"apicoaortic-pa" cannulation.

PubMed

Wada, J; Komatsu, S; Nakae, S; Kazui, T

1976-06-01

The present paper describes experimental and clinical studies of a new method "Apicoaortic-PA" cannulation for mitral valve surgery. Our experimental study showed that this method was more rapid and more physiological for cardiopulmonary bypass. We used this technique in 55 cases of isolated mitral valve surgery with successful results. Our general philosophy of surgical approach to the mitral valve diseases is also discussed. We advocate the utilization of the "Apicoaortic Pulmonary Artery" cannulation method for clinical use in isolated mitral valve surgery through the left thoracotomy.

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases*

PubMed Central

Bot, Nathalie; Schweizer, Claude; Ben Halima, Saoussen; Fraering, Patrick C.

2011-01-01

Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that α- and γ-secretases can sequentially process NRXN3β, leading to the formation of two final products, an ∼80-kDa N-terminal extracellular domain of Neurexin-3β (sNRXN3β) and an ∼12-kDa C-terminal intracellular NRXN3β domain (NRXN3β-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the γ-secretase that cause early-onset familial Alzheimer disease. PMID:21084300

Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb.

PubMed

Vaaga, Christopher E; Yorgason, Jordan T; Williams, John T; Westbrook, Gary L

2017-03-01

In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABA A receptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D 2 and GABA B receptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells. NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs. Copyright © 2017 the American Physiological Society.

Modulation of Olfactory Bulb Network Activity by Serotonin: Synchronous Inhibition of Mitral Cells Mediated by Spatially Localized GABAergic Microcircuits

ERIC Educational Resources Information Center

Schmidt, Loren J.; Strowbridge, Ben W.

2014-01-01

Although inhibition has often been proposed as a central mechanism for coordinating activity in the olfactory system, relatively little is known about how activation of different inhibitory local circuit pathways can generate coincident inhibition of principal cells. We used serotonin (5-HT) as a pharmacological tool to induce spiking in ensembles…

Parallel odor processing by mitral and middle tufted cells in the olfactory bulb.

PubMed

Cavarretta, Francesco; Burton, Shawn D; Igarashi, Kei M; Shepherd, Gordon M; Hines, Michael L; Migliore, Michele

2018-05-16

The olfactory bulb (OB) transforms sensory input into spatially and temporally organized patterns of activity in principal mitral (MC) and middle tufted (mTC) cells. Thus far, the mechanisms underlying odor representations in the OB have been mainly investigated in MCs. However, experimental findings suggest that MC and mTC may encode parallel and complementary odor representations. We have analyzed the functional roles of these pathways by using a morphologically and physiologically realistic three-dimensional model to explore the MC and mTC microcircuits in the glomerular layer and deeper plexiform layer. The model makes several predictions. MCs and mTCs are controlled by similar computations in the glomerular layer but are differentially modulated in deeper layers. The intrinsic properties of mTCs promote their synchronization through a common granule cell input. Finally, the MC and mTC pathways can be coordinated through the deep short-axon cells in providing input to the olfactory cortex. The results suggest how these mechanisms can dynamically select the functional network connectivity to create the overall output of the OB and promote the dynamic synchronization of glomerular units for any given odor stimulus.

Minimally invasive mitral valve surgery is associated with equivalent cost and shorter hospital stay when compared with traditional sternotomy.

PubMed

Atluri, Pavan; Stetson, Robert L; Hung, George; Gaffey, Ann C; Szeto, Wilson Y; Acker, Michael A; Hargrove, W Clark

2016-02-01

Mitral valve surgery is increasingly performed through minimally invasive approaches. There are limited data regarding the cost of minimally invasive mitral valve surgery. Moreover, there are no data on the specific costs associated with mitral valve surgery. We undertook this study to compare the costs (total and subcomponent) of minimally invasive mitral valve surgery relative to traditional sternotomy. All isolated mitral valve repairs performed in our health system from March 2012 through September 2013 were analyzed. To ensure like sets of patients, only those patients who underwent isolated mitral valve repairs with preoperative Society of Thoracic Surgeons scores of less than 4 were included in this study. A total of 159 patients were identified (sternotomy, 68; mini, 91). Total incurred direct cost was obtained from hospital financial records. Analysis demonstrated no difference in total cost (operative and postoperative) of mitral valve repair between mini and sternotomy ($25,515 ± $7598 vs $26,049 ± $11,737; P = .74). Operative costs were higher for the mini cohort, whereas postoperative costs were significantly lower. Postoperative intensive care unit and total hospital stays were both significantly shorter for the mini cohort. There were no differences in postoperative complications or survival between groups. Minimally invasive mitral valve surgery can be performed with overall equivalent cost and shorter hospital stay relative to traditional sternotomy. There is greater operative cost associated with minimally invasive mitral valve surgery that is offset by shorter intensive care unit and hospital stays. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Percutaneous repair or surgery for mitral regurgitation.

PubMed

Feldman, Ted; Foster, Elyse; Glower, Donald D; Glower, Donald G; Kar, Saibal; Rinaldi, Michael J; Fail, Peter S; Smalling, Richard W; Siegel, Robert; Rose, Geoffrey A; Engeron, Eric; Loghin, Catalin; Trento, Alfredo; Skipper, Eric R; Fudge, Tommy; Letsou, George V; Massaro, Joseph M; Mauri, Laura

2011-04-14

Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).

Annular dynamics of memo3D annuloplasty ring evaluated by 3D transesophageal echocardiography.

PubMed

Nishi, Hiroyuki; Toda, Koichi; Miyagawa, Shigeru; Yoshikawa, Yasushi; Fukushima, Satsuki; Yoshioka, Daisuke; Sawa, Yoshiki

2018-04-01

We assessed the mitral annular motion after mitral valve repair with the Sorin Memo 3D® (Sorin Group Italia S.r.L., Saluggia, Italy), which is a unique complete semirigid annuloplasty ring intended to restore the systolic profile of the mitral annulus while adapting to the physiologic dynamism of the annulus, using transesophageal real-time three-dimensional echocardiography. 17 patients (12 male; mean age 60.4 ± 14.9 years) who underwent mitral annuloplasty using the Memo 3D ring were investigated. Mitral annular motion was assessed using QLAB®version8 allowing for a full evaluation of the mitral annulus dynamics. The mitral annular dimensions were measured throughout the cardiac cycle using 4D MV assessment2® while saddle shape was assessed through sequential measurements by RealView®. Saddle shape configuration of the mitral annulus and posterior and anterior leaflet motion could be observed during systole and diastole. The mitral annular area changed during the cardiac cycle by 5.7 ± 1.8%.The circumference length and diameter also changed throughout the cardiac cycle. The annular height was significantly higher in mid-systole than in mid-diastole (p < 0.05). The Memo 3D ring maintained a physiological saddle-shape configuration throughout the cardiac cycle. Real-time three-dimensional echocardiography analysis confirmed the motion and flexibility of the Memo 3D ring upon implantation.

Mitral Annular Calcium and Mitral Stenosis Determined by Multidetector Computed Tomography in Patients Referred for Aortic Stenosis.

PubMed

Mejean, Simon; Bouvier, Erik; Bataille, Vincent; Seknadji, Patrick; Fourchy, Dominique; Tabet, Jean-Yves; Lairez, Olivier; Cormier, Bertrand

2016-10-15

Mitral annular calcium (MAC) is a common finding in older patients referred for transcatheter aortic valve implantation (TAVI). Multidetector computed tomography (MDCT) allows fine quantification of the calcific deposits. Our objective was to estimate the prevalence of MAC and associated mitral stenosis (MS) in patients referred for TAVI using MDCT. A cohort of 346 consecutive patients referred for TAVI evaluation was screened by MDCT for MAC: 174 had MAC (50%). Of these patients, 165 patients (95%) had mitral valve area (MVA) assessable by MDCT planimetry (age 83.8 ± 5.9 years). Median mitral calcium volume and MVA were 545 mm 3 (193 to 1,253 mm 3 ) and 234 mm 2 (187 to 297 mm 2 ), respectively. The MS was very severe, severe, and moderate in 2%, 22%, and 10% patients, respectively. By multivariate analysis, MVA was independently correlated to mitral calcium volume, aortic annular area, and some specific patterns of mitral leaflet calcium. Based on these findings, a formula was elaborated to predict the presence of a significant MS. In conclusion, MDCT allows detailed assessment of MAC in TAVI populations, demonstrating a high prevalence. Mitral analysis should become routine during MDCT screening before TAVI as it may alter therapeutic strategy. Copyright © 2016 Elsevier Inc. All rights reserved.

Resolution of massive left atrial appendage thrombi with rivaroxaban before balloon mitral commissurotomy in severe mitral stenosis: A case report and literature review.

PubMed

Li, Yuechun; Lin, Jiafeng; Peng, Chen

2016-12-01

Data on nonvitamin K antagonist oral anticoagulant being used for the treatment of LAA thrombi are limited only in nonvalvular atrial fibrillation. There are no data on the antithrombotic efficacy and safety of nonvitamin K antagonist oral anticoagulant in the resolution of left atrial appendage (LAA) thrombi in patients with rheumatic mitral stenosis. A 49-year-old woman with known rheumatic mitral stenosis and atrial fibrillation was referred for percutaneous transvenous mitral commissurotomy because of progressive dyspnea on exertion over a period of 3 months. Transesophageal echocardiography (TEE) demonstrated a large LAA thrombus protruding into left atria cavity before the procedure. Direct factor Xa (FXa) inhibitor rivaroxaban (20 mg/d) was started for the patient. After 3 weeks of rivaroxaban treatment TEE showed a relevantly decreased thrombus size, and a complete thrombus resolution was achieved after 5 weeks of anticoagulant therapy with the FXa inhibitor. To the best of our knowledge, this is the first documented case of large LAA thrombus resolution with nonvitamin K antagonist oral anticoagulant in severe mitral stenosis, and in which percutaneous transvenous mitral commissurotomy was performed subsequently. The report indicated that rivaroxaban could be a therapeutic option for mitral stenosis patients with LAA thrombus. Further study is required before the routine use of rivaroxaban in patients with rheumatic mitral stenosis and atrial fibrillation.

Intrinsic and synaptic properties of vertical cells of the mouse dorsal cochlear nucleus

PubMed Central

Kuo, Sidney P.; Lu, Hsin-Wei

2012-01-01

Multiple classes of inhibitory interneurons shape the activity of principal neurons of the dorsal cochlear nucleus (DCN), a primary target of auditory nerve fibers in the mammalian brain stem. Feedforward inhibition mediated by glycinergic vertical cells (also termed tuberculoventral or corn cells) is thought to contribute importantly to the sound-evoked response properties of principal neurons, but the cellular and synaptic properties that determine how vertical cells function are unclear. We used transgenic mice in which glycinergic neurons express green fluorescent protein (GFP) to target vertical cells for whole cell patch-clamp recordings in acute slices of DCN. We found that vertical cells express diverse intrinsic spiking properties and could fire action potentials at high, sustained spiking rates. Using paired recordings, we directly examined synapses made by vertical cells onto fusiform cells, a primary DCN principal cell type. Vertical cell synapses produced unexpectedly small-amplitude unitary currents in fusiform cells, and additional experiments indicated that multiple vertical cells must be simultaneously active to inhibit fusiform cell spike output. Paired recordings also revealed that a major source of inhibition to vertical cells comes from other vertical cells. PMID:22572947

Mitral Valve Stenosis after Open Repair Surgery for Non-rheumatic Mitral Valve Regurgitation: A Review.

PubMed

Shabsigh, Muhammad; Lawrence, Cassidy; Rosero-Britton, Byron R; Kumar, Nicolas; Kimura, Satoshi; Durda, Michael Andrew; Essandoh, Michael

2016-01-01

Mitral stenosis (MS) after mitral valve (MV) repair is a slowly progressive condition, usually detected many years after the index MV surgery. It is defined as a mean transmitral pressure gradient (TMPG) >5 mmHg or a mitral valve area (MVA) <1.5 cm(2). Pannus formation around the mitral annulus or extending to the mitral leaflets is suggested as the main mechanism for developing delayed MS after MV repair. On the other hand, early stenosis is thought to be a direct result of an undersized annuloplasty ring. Furthermore, in MS following ischemic mitral regurgitation (MR) repair, subvalvular tethering is the hypothesized pathophysiology. MS after MV repair has an incidence of 9-54%. Several factors have been associated with a higher risk for developing MS after MV repair, including the use of flexible Duran annuloplasty rings versus rigid Carpentier-Edwards rings, complete annuloplasty rings versus partial bands, small versus large anterior leaflet opening angle, and anterior leaflet tip opening length. Intraoperative echocardiography can measure the anterior leaflet opening angle, the anterior leaflet tip opening dimension, the MVA and the mean TMPG, and may help identify patients at risk for developing MS after MV repair.

Mitral Valve Stenosis after Open Repair Surgery for Non-rheumatic Mitral Valve Regurgitation: A Review

PubMed Central

Shabsigh, Muhammad; Lawrence, Cassidy; Rosero-Britton, Byron R.; Kumar, Nicolas; Kimura, Satoshi; Durda, Michael Andrew; Essandoh, Michael

2016-01-01

Mitral stenosis (MS) after mitral valve (MV) repair is a slowly progressive condition, usually detected many years after the index MV surgery. It is defined as a mean transmitral pressure gradient (TMPG) >5 mmHg or a mitral valve area (MVA) <1.5 cm2. Pannus formation around the mitral annulus or extending to the mitral leaflets is suggested as the main mechanism for developing delayed MS after MV repair. On the other hand, early stenosis is thought to be a direct result of an undersized annuloplasty ring. Furthermore, in MS following ischemic mitral regurgitation (MR) repair, subvalvular tethering is the hypothesized pathophysiology. MS after MV repair has an incidence of 9–54%. Several factors have been associated with a higher risk for developing MS after MV repair, including the use of flexible Duran annuloplasty rings versus rigid Carpentier–Edwards rings, complete annuloplasty rings versus partial bands, small versus large anterior leaflet opening angle, and anterior leaflet tip opening length. Intraoperative echocardiography can measure the anterior leaflet opening angle, the anterior leaflet tip opening dimension, the MVA and the mean TMPG, and may help identify patients at risk for developing MS after MV repair. PMID:27148540

Optimal degrees of synaptic connectivity

PubMed Central

Litwin-Kumar, Ashok; Harris, Kameron Decker; Axel, Richard; Sompolinsky, Haim; Abbott, L. F.

2017-01-01

Summary Synaptic connectivity varies widely across neuronal types. Cerebellar granule cells receive five orders of magnitude fewer inputs than the Purkinje cells they innervate, and cerebellum-like circuits including the insect mushroom body also exhibit large divergences in connectivity. In contrast, the number of inputs per neuron in cerebral cortex is more uniform and large. We investigate how the dimension of a representation formed by a population of neurons depends on how many inputs they each receive and what this implies for learning associations. Our theory predicts that the dimensions of the cerebellar granule-cell and Drosophila Kenyon-cell representations are maximized at degrees of synaptic connectivity that match those observed anatomically, showing that sparse connectivity is sometimes superior to dense connectivity. When input synapses are subject to supervised plasticity, however, dense wiring becomes advantageous, suggesting that the type of plasticity exhibited by a set of synapses is a major determinant of connection density. PMID:28215558

Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells After Spinal Cord Injury

PubMed Central

Lu, Paul; Woodruff, Grace; Wang, Yaozhi; Graham, Lori; Hunt, Matt; Wu, Di; Boehle, Eileen; Ahmad, Ruhel; Poplawski, Gunnar; Brock, John; Goldstein, Lawrence S. B.; Tuszynski, Mark H.

2014-01-01

Human induced pluripotent stem cells (iPSCs) from a healthy 86 year-old male were differentiated into neural stem cells and grafted into adult immunodeficient rats after spinal cord injury. Three months after C5 lateral hemisections, iPSCs survived and differentiated into neurons and glia, and extended tens of thousands of axons from the lesion site over virtually the entire length of the rat central nervous system. These iPSC-derived axons extended through adult white matter of the injured spinal cord, frequently penetrating gray matter and forming synapses with rat neurons. In turn, host supraspinal motor axons penetrated human iPSC grafts and formed synapses. These findings indicate that intrinsic neuronal mechanisms readily overcome the inhibitory milieu of the adult injured spinal cord to extend many axons over very long distances; these capabilities persist even in neurons reprogrammed from very aged human cells. PMID:25123310

Spatial and Temporal Control of T Cell Activation Using a Photoactivatable Agonist.

PubMed

Sanchez, Elisa; Huse, Morgan

2018-04-25

T lymphocytes engage in rapid, polarized signaling, occurring within minutes following TCR activation. This induces formation of the immunological synapse, a stereotyped cell-cell junction that regulates T cell activation and directionally targets effector responses. To study these processes effectively, an imaging approach that is tailored to capturing fast, polarized responses is necessary. This protocol describes such a system, which is based on a photoactivatable peptide-major histocompatibility complex (pMHC) that is non-stimulatory until it is exposed to ultraviolet light. Targeted decaging of this reagent during videomicroscopy experiments enables precise spatiotemporal control of TCR activation and high-resolution monitoring of subsequent cellular responses by total internal reflection (TIRF) imaging. This approach is also compatible with genetic and pharmacological perturbation strategies. This allows for the assembly of well-defined molecular pathways that link TCR signaling to the formation of the polarized cytoskeletal structures that underlie the immunological synapse.

Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts.

PubMed

Shi, Mingjian; Majumdar, Devi; Gao, Yandong; Brewer, Bryson M; Goodwin, Cody R; McLean, John A; Li, Deyu; Webb, Donna J

2013-08-07

Two novel microfluidic cell culture schemes, a vertically-layered set-up and a four chamber set-up, were developed for co-culturing central nervous system (CNS) neurons and glia. The cell chambers in these devices were separated by pressure-enabled valve barriers, which permitted us to control communication between the two cell types. The unique design of these devices facilitated the co-culture of glia with neurons in close proximity (∼50-100 μm), differential transfection of neuronal populations, and dynamic visualization of neuronal interactions, such as the development of synapses. With these co-culture devices, initial synaptic contact between neurons transfected with different fluorescent markers, such as green fluorescent protein (GFP) and mCherry-synaptophysin, was imaged using high-resolution fluorescence microscopy. The presence of glial cells had a profound influence on synapses by increasing the number and stability of synaptic contacts. Interestingly, as determined by liquid chromatography-ion mobility-mass spectrometry, neuron-glia co-cultures produced elevated levels of soluble factors compared to that secreted by individual neuron or glia cultures, suggesting a potential mechanism by which neuron-glia interactions could modulate synaptic function. Collectively, these results show that communication between neurons and glia is critical for the formation and stability of synapses and point to the importance of developing neuron-glia co-culture systems such as the microfluidic platforms described in this study.

Supravalvar mitral ring with a parachute mitral valve and subcoarctation of the aorta in a child with hemodynamically significant VSD. A study of the morphology, echocardiographic diagnostics and surgical therapy.

PubMed

Mądry, Wojciech; Karolczak, Maciej A; Grabowski, Krzysztof

2017-09-01

The authors present a case of echocardiographic diagnosis of supravalvar mitral ring (a fibromembranous structure that arose from the atrial surface of the mitral leaflets) in a child with a parachute mitral valve, a ventricular septal defect, and mild narrowing of the aortic isthmus. The supravalvar mitral stenosis is a typical but very infrequently detected element of the complex of anatomical abnormalities located within the left heart and the proximal aorta, called the Shone's complex (syndrome). Diagnosing an additional, hemodynamically significant anatomic defect during echocardiography was possible thanks to the detection of marked mobility limitation of the ring-adjacent part of the mitral valve mural leaflet as well as of an atypical image of turbulence occurring during the inflow from the left atrium to the left ventricle. The early diagnosis made it possible to perform complete correction of this complex congenital defect within a single operation.

Tissue Doppler imaging and echo-Doppler findings associated with a mitral valve stenosis with an immobile posterior valve leaflet in a bull terrier.

PubMed

Tidholm, A; Nicolle, A P; Carlos, C; Gouni, V; Caruso, J L; Pouchelon, J L; Chetboul, V

2004-04-01

A mitral valve stenosis was diagnosed in a 2-year-old female Bull Terrier by use of two-dimensional (2-D) and M-mode echocardiography, colour-flow imaging and spectral Doppler examinations. Tissue Doppler Imaging was also performed to assess the segmental radial myocardial motion. The mitral valve stenosis was characterized by a decreased mitral orifice area/left ventricle area ratio (0.14), an increased early diastolic flow velocity (E wave = 1.9 m/s), a prolonged pressure half-time (106 ms) and a decreased E-F slope (4.5 cm/s) on pulsed-wave Doppler examination. This mitral stenosis was associated with an immobile posterior leaflet, as seen on 2-D and M-mode echocardiography. Immobility of the posterior mitral leaflet is considered to be a rare finding in humans and, to our knowledge, has not been precisely documented in dogs with mitral valve stenosis.

Probe for production and measurement of acute mitral regurgitant flow in dog.

PubMed

Kléber, A G; Simon, R; Rutishauser, W

1976-02-01

A probe for production and measurement of acute mitral regurgitation in dogs is described. It consists of a tube that is introduced into the mitral valve through the left atrial appendage. Regurgitant flow through the tube is measured by an electromagnetic device. Variation of flow and zero flow are achieved by narrowing or occluding the tube with a rubber cuff. In animals weighing 30-50 kg, the probe does not produce significant mitral stenosis and the mitral leaflets fit closely around the probe during ventricular systole. The instantaneous relationship between mitral regurgitant flow (MRF) and the gradient between left ventricular and left atrial pressure shows a marked delay of MRF at the beginning and end of regurgitation. This delay can be attributed to some extent to electrical phase lag and to the small movement of the probe relative to the mitral valve during the cardiac cycle. Measurement of regurgitant stroke volume is affected by this movement only to a small extent.

Role of Imaging Techniques in Percutaneous Treatment of Mitral Regurgitation.

PubMed

Li, Chi-Hion; Arzamendi, Dabit; Carreras, Francesc

2016-04-01

Mitral regurgitation is the most prevalent valvular heart disease in the United States and the second most prevalent in Europe. Patients with severe mitral regurgitation have a poor prognosis with medical therapy once they become symptomatic or develop signs of significant cardiac dysfunction. However, as many as half of these patients are inoperable because of advanced age, ventricular dysfunction, or other comorbidities. Studies have shown that surgery increases survival in patients with organic mitral regurgitation due to valve prolapse but has no clinical benefit in those with functional mitral regurgitation. In this scenario, percutaneous repair for mitral regurgitation in native valves provides alternative management of valvular heart disease in patients at high surgical risk. Percutaneous repair for mitral regurgitation is a growing field that relies heavily on imaging techniques to diagnose functional anatomy and guide repair procedures. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Late leaflet fracture and embolization of a Duromedics mitral prosthesis.

PubMed

Sudo, K; Sasagawa, N; Ide, H; Nunokawa, M; Fujiki, T; Tonari, K

2000-08-01

A case of leaflet fracture and embolization of a mitral prosthetic valve is described. A 54-year-old man had received mitral valve replacement with an Edwards-Duromedics 29M prosthetic valve, at 10 years ago. Emergency mitral valve replacement was performed because the patient had severe congestive left heart failure with severe acute mitral regurgitation caused by a fracture in one of the mitral valve leaflets. The leaflet, which was fractured into 2 pieces, was removed from the right common iliac artery at 3 months after valve replacement. Visual inspection revealed that the leaflet contained a midline fracture. The fracture originated within a cavitary erosion pit near the major radius of the leaflet. The patient recovered from acute renal failure, requiring hemodialysis for 80 days, and is currently without complaints. We have used a Duromedics mitral valve in 11 patients, from April 1987 to April 1988. No subsequent valve failure has occurred. The diagnosis, treatment and cause of a mechanical valve fracture are discussed.

Collagen XIX Is Expressed by Interneurons and Contributes to the Formation of Hippocampal Synapses

PubMed Central

Su, Jianmin; Gorse, Karen; Ramirez, Francesco; Fox, Michael A.

2010-01-01

Extracellular matrix (ECM) molecules contribute to the formation and maintenance of synapses in the mammalian nervous system. We previously discovered a family of nonfibrillar collagens that organize synaptic differentiation at the neuromuscular junction (NMJ). Although many NMJ-organizing cues contribute to central nervous system (CNS) synaptogenesis, whether similar roles for collagens exist at central synapses remained unclear. In the present study we discovered that col19a1, the gene encoding nonfibrillar collagen XIX, is expressed by subsets of hippocampal neurons. Colocalization with the interneuron-specific enzyme glutamate decarboxylase 67 (Gad67), but not other cell-type-specific markers, suggests that hippocampal expression of col19a1 is restricted to interneurons. However, not all hippocampal interneurons express col19a1 mRNA; subsets of neuropeptide Y (NPY)-, somatostatin (Som)-, and calbindin (Calb)-immunoreactive interneurons express col19a1, but those containing parvalbumin (Parv) or calretinin (Calr) do not. To assess whether collagen XIX is required for the normal formation of hippocampal synapses, we examined synaptic morphology and composition in targeted mouse mutants lacking collagen XIX. We show here that subsets of synaptotagmin 2 (Syt2)-containing hippocampal nerve terminals appear malformed in the absence of collagen XIX. The presence of Syt2 in inhibitory hippocampal synapses, the altered distribution of Gad67 in collagen XIX-deficient subiculum, and abnormal levels of gephyrin in collagen XIX-deficient hippocampal extracts all suggest inhibitory synapses are affected by the loss of collagen XIX. Together, these data not only reveal that collagen XIX is expressed by central neurons, but show for the first time that a nonfibrillar collagen is necessary for the formation of hippocampal synapses. PMID:19937713

Permanent central synaptic disconnection of proprioceptors after nerve injury and regeneration. I. Loss of VGLUT1/IA synapses on motoneurons

PubMed Central

Titus-Mitchell, Haley E.; Bullinger, Katie L.; Kraszpulski, Michal; Nardelli, Paul; Cope, Timothy C.

2011-01-01

Motor and sensory proprioceptive axons reinnervate muscles after peripheral nerve transections followed by microsurgical reattachment; nevertheless, motor coordination remains abnormal and stretch reflexes absent. We analyzed the possibility that permanent losses of central IA afferent synapses, as a consequence of peripheral nerve injury, are responsible for this deficit. VGLUT1 was used as a marker of proprioceptive synapses on rat motoneurons. After nerve injuries synapses are stripped from motoneurons, but while other excitatory and inhibitory inputs eventually recover, VGLUT1 synapses are permanently lost on the cell body (75–95% synaptic losses) and on the proximal 100 μm of dendrite (50% loss). Lost VGLUT1 synapses did not recover, even many months after muscle reinnervation. Interestingly, VGLUT1 density in more distal dendrites did not change. To investigate whether losses are due to VGLUT1 downregulation in injured IA afferents or to complete synaptic disassembly and regression of IA ventral projections, we studied the central trajectories and synaptic varicosities of axon collaterals from control and regenerated afferents with IA-like responses to stretch that were intracellularly filled with neurobiotin. VGLUT1 was present in all synaptic varicosities, identified with the synaptic marker SV2, of control and regenerated afferents. However, regenerated afferents lacked axon collaterals and synapses in lamina IX. In conjunction with the companion electrophysiological study [Bullinger KL, Nardelli P, Pinter MJ, Alvarez FJ, Cope TC. J Neurophysiol (August 10, 2011). doi:10.1152/jn.01097.2010], we conclude that peripheral nerve injuries cause a permanent retraction of IA afferent synaptic varicosities from lamina IX and disconnection with motoneurons that is not recovered after peripheral regeneration and reinnervation of muscle by sensory and motor axons. PMID:21832035

Heterogeneity of fish taste bud ultrastructure as demonstrated in the holosteans Amia calva and Lepisosteus oculatus.

PubMed Central

Reutter, K; Boudriot, F; Witt, M

2000-01-01

Taste buds are the peripheral sensory organs of the gustatory system. They occur in all taxa of vertebrates and are pear-shaped intra-epithelial organs of about 80 microm height and 50 microm width. Taste buds mainly consist of specialized epithelial cells, which synapse at their bases and therefore are secondary sensory cells. Taste buds have been described based on studies of teleostean species, but it turned out that the ultrastructure of teleostean taste buds may differ between distinct systematic groups and that this description is not representative of those taste buds in other main taxa of fishes, such as selachians, holosteans and dipnoans. Furthermore, it is not known how variable the micromorphologies of non-teleostean taste buds are. For this reason the taste buds of two holosteans, Lepisosteus oculatus and Amia calva, were investigated and compared. While in both species the taste buds are of the same shapes and sizes, the cellular components of their sensory epithelia differ: in Lepisosteus taste buds comprise two types of elongated light cells and one type of dark cells. In contrast, Amia taste buds contain only one type of light, but two types of dark elongated cells. Afferent synapses are common in the buds of both species, efferent synapses occur only in Lepisosteus taste buds. These differences show that even in the small group of holostean fishes the taste buds are differently organized. Consequently, a representative type of fish taste buds does not exist. PMID:11079403

Heterogeneity of fish taste bud ultrastructure as demonstrated in the holosteans Amia calva and Lepisosteus oculatus.

PubMed

Reutter, K; Boudriot, F; Witt, M

2000-09-29

Taste buds are the peripheral sensory organs of the gustatory system. They occur in all taxa of vertebrates and are pear-shaped intra-epithelial organs of about 80 microm height and 50 microm width. Taste buds mainly consist of specialized epithelial cells, which synapse at their bases and therefore are secondary sensory cells. Taste buds have been described based on studies of teleostean species, but it turned out that the ultrastructure of teleostean taste buds may differ between distinct systematic groups and that this description is not representative of those taste buds in other main taxa of fishes, such as selachians, holosteans and dipnoans. Furthermore, it is not known how variable the micromorphologies of non-teleostean taste buds are. For this reason the taste buds of two holosteans, Lepisosteus oculatus and Amia calva, were investigated and compared. While in both species the taste buds are of the same shapes and sizes, the cellular components of their sensory epithelia differ: in Lepisosteus taste buds comprise two types of elongated light cells and one type of dark cells. In contrast, Amia taste buds contain only one type of light, but two types of dark elongated cells. Afferent synapses are common in the buds of both species, efferent synapses occur only in Lepisosteus taste buds. These differences show that even in the small group of holostean fishes the taste buds are differently organized. Consequently, a representative type of fish taste buds does not exist.

Neuronal and Astrocytic Monoacylglycerol Lipase Limit the Spread of Endocannabinoid Signaling in the Cerebellum.

PubMed

Chen, Yao; Liu, Xiaojie; Vickstrom, Casey R; Liu, Michelle J; Zhao, Li; Viader, Andreu; Cravatt, Benjamin F; Liu, Qing-Song

2016-01-01

Endocannabinoids are diffusible lipophilic molecules that may spread to neighboring synapses. Monoacylglycerol lipase (MAGL) is the principal enzyme that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Using knock-out mice in which MAGL is deleted globally or selectively in neurons and astrocytes, we investigated the extent to which neuronal and astrocytic MAGL limit the spread of 2-AG-mediated retrograde synaptic depression in cerebellar slices. A brief tetanic stimulation of parallel fibers in the molecular layer induced synaptically evoked suppression of excitation (SSE) in Purkinje cells, and both neuronal and astrocytic MAGL contribute to the termination of this form of endocannabinoid-mediated synaptic depression. The spread of SSE among Purkinje cells occurred only after global knock-out of MAGL or pharmacological blockade of either MAGL or glutamate uptake, but no spread was detected following neuron- or astrocyte-specific deletion of MAGL. The spread of endocannabinoid signaling was also influenced by the spatial pattern of synaptic stimulation, because it did not occur at spatially dispersed parallel fiber synapses induced by stimulating the granular layer. The tetanic stimulation of parallel fibers did not induce endocannabinoid-mediated synaptic suppression in Golgi cells even after disruption of MAGL and glutamate uptake, suggesting that heightened release of 2-AG by Purkinje cells does not spread the retrograde signal to parallel fibers that innervate Golgi cells. These results suggest that both neuronal and astrocytic MAGL limit the spatial diffusion of 2-AG and confer synapse-specificity of endocannabinoid signaling.

Predictors of survival in octogenarians after mitral valve surgery for degenerative disease: The Mitral Surgery in Octogenarians study.

PubMed

Chivasso, Pierpaolo; Bruno, Vito D; Farid, Shakil; Malvindi, Pietro Giorgio; Modi, Amit; Benedetto, Umberto; Ciulli, Franco; Abu-Omar, Yasir; Caputo, Massimo; Angelini, Gianni D; Livesey, Steve; Vohra, Hunaid A

2018-04-01

An increasing number of octogenarians are referred to undergo mitral valve surgery for degenerative disease, and percutaneous approaches are being increasingly used in this subgroup of patients. We sought to determine the survival and its predictors after Mitral Valve Surgery in Octogenarians (MiSO) in a multicenter UK study of high-volume specialized centers. Pooled data from 3 centers were collected retrospectively. To identify the predictors of short-term composite outcome of 30 days mortality, acute kidney injury, and cerebrovascular accident, a multivariable logistic regression model was developed. Multiple Cox regression analysis was performed for late mortality. Kaplan-Meier curves were generated for long-term survival in various subsets of patients. Receiver operating characteristic analysis was done to determine the predictive power of the logistic European System for Cardiac Operative Risk Evaluation. A total of 247 patients were included in the study. The median follow-up was 2.9 years (minimum 0, maximum 14 years). A total of 150 patients (60.7%) underwent mitral valve repair, and 97 patients (39.3%) underwent mitral valve replacement. Apart from redo cardiac surgery (mitral valve repair 6 [4%] vs mitral valve replacement 11 [11.3%], P = .04) and preoperative atrial fibrillation (mitral valve repair 79 [52.6%] vs mitral valve replacement 34 [35.1%], P < .01), there was no significant difference in terms of any other preoperative characteristics between the 2 groups. Patient operative risk, as estimated by logistic European System for Cardiac Operative Risk Evaluation, was lower in the mitral valve repair group (10.2 ± 11.8 vs 13.7 ± 15.2 in mitral valve replacement; P = .07). No difference was found between groups for duration of cardiopulmonary bypass and aortic crossclamp times. The 30-day mortality for the whole cohort was 13.8% (mitral valve repair 4.7% vs mitral valve replacement 18.6%; P < .01). No differences were found in terms of postoperative cerebrovascular accident (2% vs 3.1%; P = .9), acute kidney injury requiring dialysis (6.7% vs 13.4%; P = .12), and superficial or deep sternal wound infection (10% vs 16.5%, P = .17; 2% vs 3.1%, P = .67, respectively). The final multiple regression model for short-term composite outcome included previous cardiac surgery (odds ratio [OR], 4.47; 95% confidence interval [CI], 1.37-17.46; P = .02), intra-aortic balloon pump use (OR, 4.77; 95% CI, 1.67-15.79; P < .01), and mitral valve replacement (OR, 7.7; 95% CI, 4.04-14.9; P < .01). Overall survival for the entire cohort at 1, 5, and 10 years was 82.4%, 63.7%, and 45.5% (mitral valve repair vs mitral valve replacement: 89.9% vs 70.7% at 1 year, 69.6% vs 54% at 5 years, and 51.8% vs 35.5% at 10 years; P = .0005). Cox proportional hazard model results showed mitral valve replacement (hazard ratio, 1.88; 95% CI, 1.22-2.89; P < .01) and intra-aortic balloon pump use (hazard ratio, 2.54; 95% CI, 1.26-5.13; P < .01) to be independent predictor factors affecting long-term survival. Logistic European System for Cardiac Operative Risk Evaluation did not perform well in predicting early mortality (area under the curve, 0.57%). In octogenarians, mitral valve repair for degenerative disease is associated with good survival and remains the gold standard, whereas mitral valve replacement is still associated with significant mortality. Logistic European System for Cardiac Operative Risk Evaluation was unable to predict early mortality in our cohort of patients. Larger international multicenter registries are required to optimize the decision-making process in such a high-risk subgroup. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Comparative studies on glutamate decarboxylase and choline acetyltransferase activities in the vertebrate vestibule.

PubMed

López, I; Meza, G

1990-01-01

1. Vestibular putative neurotransmitters GABA and acetylcholine synthesizing enzymes were quantified in four vertebrate species to find a correlation between all-vertebrate vestibular hair cell II (HCII) and synaptic contacts and appearance of hair cell I (HCI) and related synapses in terrestrial species. 2. Glutamate decarboxylase (GAD) and choline acetyltransferase (ChAT) values were: 3.76; 15.38; 21.68; 27.78 and 9.44; 450; 720; 970 n(pico)mol/mg protein/hr (min) in, respectively, frogs, guinea pigs, rats and chicks. 3. GAD and ChAT omnipresence may indicate constant GABAergic HCII and its cholinergic efferent synapses, their raised content, appearance of GABA-containing HCI and related cholinergic boutons in higher vertebrates.

Mitral Valve Surgery in Patients with Systemic Lupus Erythematosus

PubMed Central

Hekmat, Manouchehr; Ghorbani, Mohsen; Ghaderi, Hamid; Majidi, Masoud; Beheshti, Mahmood

2014-01-01

Valvular heart disease is the common cardiac manifestation of systemic lupus erythematosus (SLE) with a tendency for mitral valve regurgitation. In this study we report a case of mitral valve replacement for mitral stenosis caused by Libman-Sacks endocarditis in the setting of SLE. In addition, we provide a systematic review of the literature on mitral valve surgery in the presence of Libman-Sacks endocarditis because its challenge on surgical options continues. Surgical decision depends on structural involvement of mitral valve and presence of active lupus nephritis and antiphospholipid antibody syndrome. Review of the literature has also shown that outcome is good in most SLE patients who have undergone valvular surgery, but association of antiphospholipid antibody syndrome with SLE has negative impact on the outcome. PMID:25401131

Complete Transversal Disc Fracture in a Björk-Shiley Delrin Mitral Valve Prosthesis 43 Years After Implantation.

PubMed

González-Santos, Jose María; Arnáiz-García, María Elena; Dalmau-Sorlí, María José; Sastre-Rincón, Jose Alfonso; Hernández-Hernández, Jesús; Pérez-Losada, María Elena; Sagredo-Meneses, Víctor; López-Rodríguez, Javier

2016-10-01

A patient who underwent previous implantation of a mitral valve replacement with a Björk-Shiley Delrin (BSD) mitral valve prosthesis during infancy was admitted to our institution 43 years later after an episode of syncope and cardiac arrest. Under extreme hemodynamic instability, a mitral valve prosthetic dysfunction causing massive mitral regurgitation was identified. The patient underwent an emergent cardiac operation, and a complete disc fracture with partial disc migration was found. Exceptional cases of mechanical prosthetic heart valve fracture exist. We report the first case of complete transversal disc rupture of a BSD mitral valve prosthesis after the longest period of implantation ever reported in that position. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

A cerebellar learning model of vestibulo-ocular reflex adaptation in wild-type and mutant mice.

PubMed

Clopath, Claudia; Badura, Aleksandra; De Zeeuw, Chris I; Brunel, Nicolas

2014-05-21

Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions. Copyright © 2014 the authors 0270-6474/14/347203-13$15.00/0.

Surgical treatment of moderate ischemic mitral regurgitation.

PubMed

Smith, Peter K; Puskas, John D; Ascheim, Deborah D; Voisine, Pierre; Gelijns, Annetine C; Moskowitz, Alan J; Hung, Judy W; Parides, Michael K; Ailawadi, Gorav; Perrault, Louis P; Acker, Michael A; Argenziano, Michael; Thourani, Vinod; Gammie, James S; Miller, Marissa A; Pagé, Pierre; Overbey, Jessica R; Bagiella, Emilia; Dagenais, François; Blackstone, Eugene H; Kron, Irving L; Goldstein, Daniel J; Rose, Eric A; Moquete, Ellen G; Jeffries, Neal; Gardner, Timothy J; O'Gara, Patrick T; Alexander, John H; Michler, Robert E

2014-12-04

Ischemic mitral regurgitation is associated with increased mortality and morbidity. For surgical patients with moderate regurgitation, the benefits of adding mitral-valve repair to coronary-artery bypass grafting (CABG) are uncertain. We randomly assigned 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus mitral-valve repair (combined procedure). The primary end point was the left ventricular end-systolic volume index (LVESVI), a measure of left ventricular remodeling, at 1 year. This end point was assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized as the lowest LVESVI rank. At 1 year, the mean LVESVI among surviving patients was 46.1±22.4 ml per square meter of body-surface area in the CABG-alone group and 49.6±31.5 ml per square meter in the combined-procedure group (mean change from baseline, -9.4 and -9.3 ml per square meter, respectively). The rate of death was 6.7% in the combined-procedure group and 7.3% in the CABG-alone group (hazard ratio with mitral-valve repair, 0.90; 95% confidence interval, 0.38 to 2.12; P=0.81). The rank-based assessment of LVESVI at 1 year (incorporating deaths) showed no significant between-group difference (z score, 0.50; P=0.61). The addition of mitral-valve repair was associated with a longer bypass time (P<0.001), a longer hospital stay after surgery (P=0.002), and more neurologic events (P=0.03). Moderate or severe mitral regurgitation was less common in the combined-procedure group than in the CABG-alone group (11.2% vs. 31.0%, P<0.001). There were no significant between-group differences in major adverse cardiac or cerebrovascular events, deaths, readmissions, functional status, or quality of life at 1 year. In patients with moderate ischemic mitral regurgitation, the addition of mitral-valve repair to CABG did not result in a higher degree of left ventricular reverse remodeling. Mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation but an increased number of untoward events. Thus, at 1 year, this trial did not show a clinically meaningful advantage of adding mitral-valve repair to CABG. Longer-term follow-up may determine whether the lower prevalence of mitral regurgitation translates into a net clinical benefit. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson's Disease

PubMed Central

Herrera-Valdez, Marco A.; Lopez-Huerta, Violeta Gisselle; Galarraga, Elvira

2015-01-01

Most neurons in the striatum are projection neurons (SPNs) which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP) between fast-spiking (FS) interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing), in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings. PMID:26167304

GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction.

PubMed

Saha, Rinki; Knapp, Stephanie; Chakraborty, Darpan; Horovitz, Omer; Albrecht, Anne; Kriebel, Martin; Kaphzan, Hanoch; Ehrlich, Ingrid; Volkmer, Hansjürgen; Richter-Levin, Gal

2017-01-01

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit.

PubMed

Hawkins, Sara J; Weiss, Lukas; Offner, Thomas; Dittrich, Katarina; Hassenklöver, Thomas; Manzini, Ivan

2017-01-01

Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks.

Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit

PubMed Central

Hawkins, Sara J.; Weiss, Lukas; Offner, Thomas; Dittrich, Katarina; Hassenklöver, Thomas; Manzini, Ivan

2017-01-01

Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks. PMID:29234276

The interplay between neurons and glia in synapse development and plasticity.

PubMed

Stogsdill, Jeff A; Eroglu, Cagla

2017-02-01

In the brain, the formation of complex neuronal networks amenable to experience-dependent remodeling is complicated by the diversity of neurons and synapse types. The establishment of a functional brain depends not only on neurons, but also non-neuronal glial cells. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This article reviews important findings, which uncovered cellular and molecular aspects of the neuron-glia cross-talk that govern the formation and remodeling of synapses and circuits. In vivo evidence demonstrating the critical interplay between neurons and glia will be the major focus. Additional attention will be given to how aberrant communication between neurons and glia may contribute to neural pathologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Problem: Mitral Valve Regurgitation

MedlinePlus

... each time the left ventricle contracts. Watch an animation of mitral valve regurgitation A leaking mitral valve ... Not Alone Popular Articles 1 Understanding Blood Pressure Readings 2 Sodium and Salt 3 Heart Attack Symptoms ...

Subacute Staphylococcus epidermidis Bacterial Endocarditis Complicated by Mitral-Aortic Intervalvular Fibrosa Pseudoaneurysm

DTIC Science & Technology

2012-12-01

Staphylococcus epidermidis Bacterial Endocarditis Complicated byMitral-Aortic Intervalvular Fibrosa Pseudoaneurysm Diane Elegino-Steffens,1 Amy Stratton,1... endocarditis . 1. Introduction The mitral-aortic intervalvular fibrosa (MAIF), also known as the mitral-aortic membrane, is a fibrous region of the heart...of his aortic valve for severe aortic regurgitation that was subsequently found to have infective endocarditis prompting antibiotic treatment. His

Evolution of the concept and practice of mitral valve repair

PubMed Central

Tchantchaleishvili, Vakhtang; Rajab, Taufiek K.

2015-01-01

The first successful mitral valve repair was performed by Elliot Cutler at Brigham and Women’s Hospital in 1923. Subsequent evolution in the surgical techniques as well as multi-disciplinary cooperation between cardiac surgeons, cardiologists and cardiac anesthesiologists has resulted in excellent outcomes. In spite of this, the etiology of mitral valve pathology ultimately determines the outcome of mitral valve repair. PMID:26309840

Ca2+-induced uncoupling of Aplysia bag cell neurons.

PubMed

Dargaei, Zahra; Standage, Dominic; Groten, Christopher J; Blohm, Gunnar; Magoski, Neil S

2015-02-01

Electrical transmission is a dynamically regulated form of communication and key to synchronizing neuronal activity. The bag cell neurons of Aplysia are a group of electrically coupled neuroendocrine cells that initiate ovulation by secreting egg-laying hormone during a prolonged period of synchronous firing called the afterdischarge. Accompanying the afterdischarge is an increase in intracellular Ca2+ and the activation of protein kinase C (PKC). We used whole cell recording from paired cultured bag cell neurons to demonstrate that electrical coupling is regulated by both Ca2+ and PKC. Elevating Ca2+ with a train of voltage steps, mimicking the onset of the afterdischarge, decreased junctional current for up to 30 min. Inhibition was most effective when Ca2+ entry occurred in both neurons. Depletion of Ca2+ from the mitochondria, but not the endoplasmic reticulum, also attenuated the electrical synapse. Buffering Ca2+ with high intracellular EGTA or inhibiting calmodulin kinase prevented uncoupling. Furthermore, activating PKC produced a small but clear decrease in junctional current, while triggering both Ca2+ influx and PKC inhibited the electrical synapse to a greater extent than Ca2+ alone. Finally, the amplitude and time course of the postsynaptic electrotonic response were attenuated after Ca2+ influx. A mathematical model of electrically connected neurons showed that excessive coupling reduced recruitment of the cells to fire, whereas less coupling led to spiking of essentially all neurons. Thus a decrease in electrical synapses could promote the afterdischarge by ensuring prompt recovery of electrotonic potentials or making the neurons more responsive to current spreading through the network. Copyright © 2015 the American Physiological Society.

Transaortic edge-to-edge mitral valve repair for moderate secondary/functional mitral regurgitation in patients undergoing aortic root/valve intervention.

PubMed

Choudhary, Shiv Kumar; Abraham, Atul; Bhoje, Amol; Gharde, Parag; Sahu, Manoj; Talwar, Sachin; Airan, Balram

2017-11-01

The present study evaluates the feasibility, safety, and efficacy of edge-to-edge repair for moderate secondary/functional mitral regurgitation in patients undergoing aortic valve/root interventions. Sixteen patients underwent transaortic edge-to-edge mitral valve repair. Mitral regurgitation was 2+ in 8 patients and 3+ in 6 patients. Two patients in whom cardiac arrest developed preoperatively had severe (4+) mitral regurgitation. Patients underwent operation for severe aortic regurgitation ± aortic root lesions. The mean left ventricular systolic and diastolic diameters were 51.5 ± 12.8 mm and 70.7 ± 10.7 mm, respectively. Left ventricular ejection fraction ranged from 20% to 60%. Primary surgical procedure included Bentall's ± hemiarch replacement in 10 patients, aortic valve replacement in 5 patients, and noncoronary sinus replacement with aortic valve repair in 1 patient. Severity of mitral regurgitation decreased to trivial or zero in 13 patients, 1+ in 2 patients, and 2+ in 1 patient. There were no gradients across the mitral valve in 9 patients, less than 5 mm Hg in 6 patients, and 9 mm Hg in 1 patient. There was no operative mortality. Follow-up ranged from 2 weeks to 54 months. Echocardiography showed trivial or no mitral regurgitation in 12 patients, 1+ in 2 patients, and 2+ in 2 patients. None of the patients had significant mitral stenosis. The mean left ventricular systolic and diastolic diameters decreased to 40.5 ± 10.3 mm and 58.7 ± 11.6 mm, respectively. Ejection fraction also improved slightly (22%-65%). Transaortic edge-to-edge mitral valve repair is a safe and effective technique to abolish secondary/functional mitral regurgitation. However, its impact on overall survival needs to be studied. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.