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High-level inhibition of mitochondrial complexes III and IV is required to increase glutamate release from the nerve terminal

High-level inhibition of mitochondrial complexes III and IV is required to increase glutamate release from the nerve terminal

Complexes III and IV have been shown to have high thresholds of inhibition of activity before major changes in oxygen consumption and ATP production occur in isolated brain mitochondria [29,30]. Comparison of such data obtained from experiments carried out on isolated nerve terminal mitochondria [31] with nonsynaptic mitochondria [32,33] indicate the threshold levels are higher in synaptosomal mitochondria for both complex III and complex IV respectively. This suggests that com- plexes III and IV have relatively low levels of control over oxidative phosphorylation in isolated synaptosomal mitochondria. Recently we demonstrated that both com- plex III and complex IV have lower control over oxygen consumption in in situ synaptosomal mitochondria than complex I [27]. To examine the control of complexes III and IV over glutamate release from nerve terminals, experiments using ranges of concentrations of the com- plex III inhibitors myxothiazol and antimycin A, which inhibit complex III activity upstream and downstream of the Q-cycle respectively [34], and a range of concentra- tions of the complex IV inhibitor KCN on glutamate release rates were carried out. Such data may be rele- vent to elucidating the role of excitotoxicity in the pathogenesis of neurodegenerative disorders.
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Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus

Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus

Results: Immunolabeling specific subsets of synapses with antibodies against vesicle-associated neurotransmitter transporters or neurotransmitter synthesizing enzymes revealed significant differences in the composition, distribution and morphology of nonretinal terminals in dLGN, vLGN and IGL. For example, inhibitory terminals are more densely packed in vLGN, and cortical terminals are more densely distributed in dLGN. Overall, synaptic terminal density appears least dense in IGL. Similar nuclei-specific differences were observed for retinal terminals using immunolabeling, genetic labeling, axonal tracing and serial block face scanning electron microscopy: retinal terminals are smaller, less morphologically complex, and more densely distributed in vLGN than in dLGN. Since glutamatergic terminal size often correlates with synaptic function, we used in vitro whole cell recordings and optic tract stimulation in acutely prepared thalamic slices to reveal that excitatory postsynaptic currents (EPSCs) are considerably smaller in vLGN and show distinct responses following paired stimuli. Finally, anterograde labeling of retinal terminals throughout early postnatal development revealed that anatomical differences in retinal nerve terminal structure are not observable as synapses initially formed, but rather developed as retinogeniculate circuits mature.
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Anti ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

Anti ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

In the Guillain-Barré syndrome subform acute motor axonal neuropathy (AMAN), Campylobacter jejuni enteritis triggers the production of anti-ganglioside Abs (AGAbs), leading to immune-mediated injury of distal motor nerves. An important question has been whether injury to the presynaptic neuron at the neuromuscular junction is a major factor in AMAN. Although disease modeling in mice exposed to AGAbs indicates that complement- mediated necrosis occurs extensively in the presynaptic axons, evidence in humans is more limited, in comparison to the extensive injury seen at nodes of Ranvier. We considered that rapid AGAb uptake at the motor nerve terminal membrane might attenuate complement- mediated injury. We found that PC12 rat neuronal cells rapidly internalized AGAb, which were trafficked to recycling endosomes and lysosomes. Consequently, complement- mediated cytotoxicity was attenuated. Importantly, we observed the same AGAb
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Complex I is rate limiting for oxygen consumption in the nerve terminal

Complex I is rate limiting for oxygen consumption in the nerve terminal

sumption in nerve terminal mitochondria. The FCC value for complex I (0.30 ⫾ 0.07) was higher than those for complex II/III (0.20 ⫾ 0.03), complex III (0.20 ⫾ 0.05), and complex IV (0.08⫾ 0.02), and the complex I inhibition threshold level (⬃10%) was lower than those for complex II/III ( ⬃ 30%), complex III (⬃35%), and complex IV (50 – 65%). Considering the observa- tion that neuronal cells cannot function anaerobically when operating at maximal glycolytic rates (24), impaired activity of the respiratory chain complexes (above the threshold levels) may reduce oxygen consumption in the nerve terminal, with subsequent reductions in ATP (11, 12). Decreased activity of respiratory complexes has been reported in numerous neuro- degenerative disorders (1– 6). The lower inhibition threshold for complex I implies that complex I defects may have the great- est ability, of the ETC complexes examined, to induce a reduced bioenergetic status in the nerve terminal. A 40% reduction in complex I activity, such as that present in PD, would reduce oxygen consumption in the nerve terminal by ⬃ 60%.
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Monoclonal antibodies raised against Guillain Barré syndrome–associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle nerve preparations

Monoclonal antibodies raised against Guillain Barré syndrome–associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle nerve preparations

The IgM mAb’s that we cloned are all similar in their ganglioside specificity and very closely resemble the human IgM antibodies associated with a chronic MFS- like syndrome, in that they bind promiscuously to NeuNAc(α2–8)NeuNAc–configured disialylated gan- gliosides including GD3, GT1a, and GQ1b, but not to monosialylated gangliosides such as GM1 (16). Equiv- alent human mAb’s are found as IgM monoclonal gammopathies in patients with chronic autoimmune neuropathies with phenotypic similarities to MFS (16). We have previously shown that one such human anti- disialosyl IgM mAb, termed Ha1, binds to many peripheral nerve sites, including motor nerve terminals (16), and blocks the mouse phrenic nerve hemidi- aphragm preparation in an α-latrotoxin–like, comple- ment-dependent manner, as is also seen with anti- GQ1b/GT1a antibody–containing MFS sera and IgG fractions (18). This electrophysiological pattern of nerve terminal block is identical to the effects we observed with CGM3-5 and further indicates that we have created LPS-induced, ganglioside cross-reactive mouse mAb’s that are equivalent to our human mAb, Ha1. Furthermore, the deposition of CGM3-5 and acti- vated complement components at the motor nerve ter- minal is identical to the immunodeposition pattern we have previously observed for anti-GQ1b/GT1a–con- taining MFS sera and Ha1 (18).
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Arthritis and pain  Future targets to control osteoarthritis pain

Arthritis and pain Future targets to control osteoarthritis pain

targeted for pain control. The mammalian TRP channel represents a large receptor family, subdivided into six subfamilies: TRPA, TRPC, TRPM, TRPP, TRPV, and mucolipin. Many TRP channels are localized to sensory neurones and play a major role in temperature and mechanical transduction. TRPV1 is a non-selective cation channel, gated by capsaicin, noxious heat (>45°C), acidic pH (<5.3), and regulated by a variety of inflammatory agents, including protons, bradykinin, ATP, PGE2, 12-lipoxygenase products, protease-activated receptor-2, anandamide, CCL3 and NGF. Sensitization of TRPV1 involves a variety of pathways that regulate receptor phosphorylation [96]. Analgesia approaches in OA have used capsaicin preparations or capsaicin-like agonists to induce TRPV1 desensitization or reversible sensory nerve terminal degeneration caused by prolonged cation influx into the nerve, osmotic damage and metabolic collapse [97]. In a randomized study of intra-articular injections of placebo or capsaicin (ALGRX 4975) prior to knee replacement, ALGRX 4975 was found to decrease visual analogue scales (VAS) scores without effecting proprioreception or joint histopathology [98]. Currently, there is a focus on TRPV1 channel blockers or selective TRPV1 receptor antagonists [99]. Supporting these approaches, competitive (AMG-9810) [100] and non-competitive (DD161515) [99] TRPV1 antagonists block chemical and thermal pain sensitivity, heralding the emergence of a novel therapy. Indeed, recent studies in volunteers have shown that oral SB705498 attenuated capsaicin and ultra-violet (UV)-induced pain and hyperalgesia [101]. Other TRP channels (TRPV3, TRPV4, TRPA1) have also been suggested to be involved in pain transduction. Thus, TRPA1 (ANKTM1) is co-localized with TRPV1 and is activated by capsaicin and mustard oil but can also be sensitized by inflammatory mediators, including bradykinin, known to be significantly elevated in osteoarthritic synovial fluid, to produce cold-induced burning pain [102]. In addition, TRPV1 can oligomerize with other TRP family members, including TRPV3. The latter is found in keratinocytes and appears to be upregulated in inflammatory pain conditions. So far there are few reliable chemical tools to help characterize the functions of these TRP receptors and support their value as analgesia targets.
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Dynamic remodelling of synapses can occur in the absence of the parent cell body

Dynamic remodelling of synapses can occur in the absence of the parent cell body

Available data points to a degree of synaptic independ- ence in the retraction of individual synaptic connections. Observations of single motor units during developmental synapse elimination reveal three quite separate popula- tions of nerve terminals: stable, actively withdrawing and actively enlarging [3,12] and it is difficult to envisage how a single cell soma could directly co-ordinate this range of actions in different parts of its terminal arbour. Adult axons and terminals appear to contain little if any machinery for protein synthesis, but the first signs of regenerative sprouting occurs within a day of axotomy [20,21], which appears too rapid for communication from the site of injury to the cell body and back, even by fast axonal transport. Neonatal synapse elimination can proceed subsequent to axotomy [6] and co-ordinated structural changes at presynaptic nerve terminals (retrac- tion) can occur in the absence of parent cell somas. Axons disconnected from their cell bodies in vitro can assemble new growth cones at lesion sites [22-24] and transected axons are able to mount a regenerative response in the absence of cell somas [25]. Taken together these data sug- gest that the machinery necessary to drive synapse loss (and re-growth) may be constitutively present in the nerve terminal and axon and that communication with the cell body is unnecessary. Although other evidence, primarily from the hippocampus, demonstrates that long-term alterations in synaptic strength at subsets of neurones in a synaptic field may be driven by pre-existing or newly syn- thesised plasticity related proteins which differentially bind to synapses dependent upon their level of activity.
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Neuromuscular Facilitation in Crayfish: Dependence on Potassium and Strophanthidin

Neuromuscular Facilitation in Crayfish: Dependence on Potassium and Strophanthidin

This long-term facilitation LTF apparently results from an increase in presynaptic transmitter release which is associated with an accumulation of sodium in the nerve terminal Atwood, Sw[r]

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Analysis of repolarization of presynaptic motor terminals in Drosophila larvae using potassium channel blocking drugs and mutations

Analysis of repolarization of presynaptic motor terminals in Drosophila larvae using potassium channel blocking drugs and mutations

Because the onset of transmitter release occurs during the repolarizing phase of the nerve terminal, measurements of synaptic latency can be used to compare the effects of different drug[r]

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PBB 71 845 pdf

PBB 71 845 pdf

The above considerations indicate that a finding of decreased concentration of brain SERT by a neuroimaging procedure in the brain of a subject exposed chronically to a neuroactive drug can be suggestive, but should not be taken as definitive proof of reduced number of serotonin neurons. More ‘‘definitive’’ proof of neuronal damage in a con- dition restricted to damage to nerve terminals (no cell body loss) can only be obtained by postmortem brain examina- tion, in which levels of all markers of serotonin nerve terminal integrity—serotonin, tryptophan hydroxylase, and SERT—are decreased if nerve terminal loss has occurred. In addition, if the interval between last exposure to the drug and death has not been prolonged, histopathological proce- dures can be utilized to demonstrate the qualitative signs of acute neuronal damage (the gold standard), namely silver staining (Switzer, 2000) and swollen, fragmented axonal elements. At the same time, however, it needs to be emphasized that all morphological procedures to assess such signs of neuronal damage rely on the very neuro- chemical markers (serotonin, tryptophan hydroxylase, and SERT) that, as discussed above, can be regulated independ- ently of changes in neuronal number. Because of this potential confound it can be argued that, on theoretical grounds, interpretation of studies of serotonin nerve ter- minal damage (without loss of cell bodies) employing neurochemical serotonergic markers will always be difficult.
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Complement activation at the motor end-plates in amyotrophic lateral sclerosis

Complement activation at the motor end-plates in amyotrophic lateral sclerosis

nerve terminal (RM-911-S/Thermo Scientific, USA, or M0776/Dako, Carpinteria, CA), anti-S100b recognizing the terminal Schwann cells (Z0311/Dako, Carpinteria, CA or S2532/Sigma, USA), anti-C5b-9 for MAC (aE11 clone, Dako, Carpinteria, CA), anti-C1q-FITC conju- gated (DAKO, Denmark), anti-C3c-FITC conjugated rec- ognizing C3c part of C3 and C3b, anti-DAF-FITC conjugated detecting the regulator of complement CD55 (BD Pharmingen), and anti-CD59 detecting the regulator of MAC (Hycult Biotech). The sections were washed in PBS, and secondary antibodies was applied, diluted ac- cording to Table 4 in blockmix, and incubated for 2 h at RT. Used secondary antibodies are anti-mouse FITC (Jackson Immunoresearch, West Grove, PA), anti-rabbit and anti-mouse Cy3 (Jackson Immuno Research, West Grove, PA), and anti-mouse Cy5 (Invitrogen, Germany). After washing off the secondary antibody, α-bungarotoxin (α-BTX)-Alexa 488 conjugate (Molecular Probes) (1:500), which binds to post-synaptic acetylcholine receptors on the muscle fibers, was applied for 20 min at room temperature to the sections to visualize the end-plates. The sections then were washed in PBS and air-dried. Vectashield medium (Vector Laboratories Inc, Burlingame, USA) was used for mounting.
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Primary and Secondary Regulation of Quantal Transmitter Release: Calcium and Sodium

Primary and Secondary Regulation of Quantal Transmitter Release: Calcium and Sodium

The current view of the processes involved in evoked transmitter release can be summarized as follows: the invasion of the nerve terminal by the action potential causes a depolarization [r]

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Physiology and Structure of Three New Uropod Proprioceptors in the Crayfish Procambarus Clarkii

Physiology and Structure of Three New Uropod Proprioceptors in the Crayfish Procambarus Clarkii

The PEnCO is a distinct strand chordotonal organ, while the APCO and PExCO are webbed structures arising from peripheral nerve roots 2 and 3 of the terminal abdominal ganglion, in which [r]

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Selective Vulnerability of Nerve Demyelination in Chronic Acquired Multifocal Polyneuropathy

Selective Vulnerability of Nerve Demyelination in Chronic Acquired Multifocal Polyneuropathy

MMN and LSS were characterized by male predominant, upper limb onset and different sensory involvement [14-17]. In this study we also found a male predominant composition in the MMN group and LSS group and it was different in the CIDP-CB group. High upper limb onset proportion and rare sensory involvement in MMN were also proved and could help in differentiating CIDP-CB. In addition, we found MMN presented slowly progressive long duration, low CSF protein and frequent positive anti-GM1, while LSS and CIDP presented progressive duration, moderate-high CSF protein and rare positive anti-GM1. Clinical findings were confirmatory and consistent with previous study [18,19]. Using electrophysiological indicators, we presented a horizontal comparison of LSS, MMN and CIDP-CB nerves. Selective vulnerability of nerve is particularly interesting and controversial in focal neuropathy. Ulnar nerve has been suggested useful in diagnosing acute demyelinating neuropathy [20], and tibial nerve was hypothesized to be especially involved in MMN [21], while other study found no difference in CB distribution [22]. In this study, noting that wrist to elbow segment of ulnar nerve conduction was least likely to be blocked in CIDP- CB compared to LSS, while the CB likelihood of segment around ulnar was vice versa in CIDP-CB compared to MMN. Another CB distribution characteristic we found was the frequent tibial nerve CB in MMN. Although upper limb is more frequently affected in
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<p>Effect of Peritumoral Bupivacaine on Primary and Distal Hyperalgesia in Cancer-Induced Bone Pain</p>

<p>Effect of Peritumoral Bupivacaine on Primary and Distal Hyperalgesia in Cancer-Induced Bone Pain</p>

CIBP-induced primary pressure hyperalgesia was completely blocked by peritumoral bupivacaine at all-time points in the study. This was expected, primarily because bupivacaine, a known local anesthetic, blocks voltage-sensitive sodium channels in the peripheral axons and inhibits the generation of afferent signals. 43 In contrast, the effect of bupivacaine on CIBP-induced distal punctate hyperalgesia was quite different; early distal hyperalgesia was reversed by bupivacaine, while late distal hyperalgesia was not. This is interesting because it highlights the difference in the underlying cellular mechanism that is involved in the manifestation of early and late distal hyperalgesia. Early distal hyperalgesia appears to be asso- ciated with alteration in the sensitivity of distal peripheral neurons secondary to changes within the bone-nerve term- inals, and not due to changes in the central nervous system. This was supported by the absence of ATF3 and GFAP expres- sion in the lumbar DRG and spinal cord lamina of day 7 PTI rats, respectively (data not shown). However, late distal hyper- algesia appears to be more associated with central neuronal changes consistent with neuropathic mechanisms, as observed by the increase in ATF3 and GFAP expression in DRG and spinal cord lamina of day 14 PTI rats. This may also explain the non-responsiveness of late distal hyperalgesia to the peri- tumoral injection of bupivacaine. Here, it is important to add that ATF3, a member of the activating transcription factor/ cAMP- responsive element binding protein (ATF/CREB) family of transcription factors, is known to be overexpressed in neurons under cellular stress. 44 Similarly, GFAP, a glial intermediate fi lament protein shows increased expression in activated astrocytes, and is commonly used as a marker of central sensitization in neuropathic pain conditions. 45
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PubMedCentral-PMC5403115.pdf

PubMedCentral-PMC5403115.pdf

In mouse, the orbits are oriented slightly laterally (Fig. 2B), and the position changes slightly as the embryo grows, so further anatomic descriptions are in reference to the eye. By E13.5, orbit growth requires that orbital dissections be performed from either the superior (looking down from above) or inferior view (looking up from below; see schematic Figs. 2C, 2D). In E13.5 wild-type embryos, the EOMs continue to grow and separate. The medial origin of the IO muscle is now evident (Figs. 3A, 3C). The distal aspect of CN4 widens considerably, and terminal branches emanate into the SO muscle from one- half of the decision region, while branches from the other half are oriented away from the muscle (Figs. 3A, 3A 0 ). Multiple branches of the CN3 superior division extend from the main
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Multiple functions of non-hypophysiotropic gonadotropin releasing hormone neurons in vertebrates

Multiple functions of non-hypophysiotropic gonadotropin releasing hormone neurons in vertebrates

Gonadotropin releasing hormone (GnRH) was first iden- tified as a peptide that is released from hypothalamic neurons at their axon terminal in the pituitary or the median eminence, and which promotes the secretion of luteinizing hormone [1–3]. It is now known that most vertebrates have three paralogous genes for GnRH (gnrh1–3). In the brain, gnrh1 is expressed in the hypo- thalamus/preoptic area, gnrh2 in the midbrain tegmen- tum, and gnrh3 in the terminal nerve neurons [4–6] (Fig. 1). GnRH-expressing neurons in the midbrain teg- mentum and the terminal nerve project their axons broadly in the brain, except the pituitary. It has also been reported that GnRH2 and GnRH3 immuno- reactive fibers project as far as to the spinal cord [5, 7, 8], and that gnrh3-expressing neurons can be found in the trigeminal nerve [7, 9]. It should be noted that some species have lost one or two gnrh paralogues, and in spe- cies that have lost either gnrh1 or gnrh3, the remaining one is expressed compensatorily in the brain region, where the lost paralogue had originally been expressed [8, 10–13] (functional compensation for the loss of a GnRH paralogue [4]). For example, zebrafish lost gnrh1, and zebrafish gnrh3 is expressed not only in the terminal nerve, but also in the preoptic area. Because all GnRH subtypes can activate all subtypes of GnRH receptors [14, 15], it is functionally important for animals that neurons projecting to a specific brain region (pituitary, median eminence, sensory processing region, etc.) ex- press one of the three gnrh paralogues.
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A Study on Patchavatham (பட்ச வாதம்)

A Study on Patchavatham (பட்ச வாதம்)

APPLIED PHYSIOLOGICAL ANATOMY OF THE NERVOUS SYSTEM The central nervous system consists of vast numbers of neurons, both afferent and efferent. A neuron is a nerve cell with its dentrites and axon. The nerve cells are found in the gray mater of the cortex, basal ganglion and nuclei. The central gray mater of the spinal cord and in posterior root ganglion. The axons are collected into bundles or tracts and run mostly in the white mater and peripheral nerves. The nerves impulse travels at different rates in different nerves. A synapse or junction between two neurons will allow an impulse to pass one direction only. At the synapse a chemical change occurs acetyl choline may be released. In central synapses by the passage of the impulse and is split by an enzyme cholinesterase. This effect is also observed at the end organs of may peripheral neurons (e.g) neuromuscvlar junction. Not all central synapses however are cholinergic, the mediator in non-cholinergic synapses is not known.
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Distribution of terminal nerve entry points to the flexor and extensor groups of forearm muscles: an anatomical study

Distribution of terminal nerve entry points to the flexor and extensor groups of forearm muscles: an anatomical study

The motor points of the skeletal muscles, mainly of interest to anatomists and physiologists, have recently attracted much attention from researchers in the field of functional electrical stimulation. The muscle motor point has been de- fined as the entry point of the motor nerve branch into the epimysium of the muscle belly. Anatomists have pointed out that many muscles in the limbs have multiple motor points. Knowledge of the location of nerve branches and termi- nal nerve entry points facilitates the exact insertion and the suitable selection of the number of electrodes required for each muscle for functional electrical stim- ulation. The present work therefore aimed to describe the number, location, and distribution of motor points in the human forearm muscles to obtain opti- mal hand function in many clinical situations.
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Quantitative analysis of the terminal branches of facial nerve in fresh frozen head and neck specimens

Quantitative analysis of the terminal branches of facial nerve in fresh frozen head and neck specimens

The terminal branches of the facial nerve are very thin and in formalin fixed cadavers, it is very difficult to find them. Secondly; for transmission electron microscopic examination of these branches; fresh or fresh frozen human samples are necessary. Therefore; in this study, they were examined in fresh frozen head and neck specimens. The first aim of this study was the quantification of nerve fibres found in the termi- nal branches of facial nerve and the second aim was the ultrastructural analysis of these terminal branches in order to observe their ultrastructural differences, if present. In the examination of literature; we could not find any studies related to this subject.
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