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David S. Holder - One of the best experts on this subject based on the ideXlab platform.

  • T15. Imaging fast Neuronal Depolarization in 3D during seizures with electrical impedance tomography and scalp and intracranial depth electrodes
    Clinical Neurophysiology, 2018
    Co-Authors: Anna Witkowska-wrobel, Kirill Aristovich, James Avery, Mayo Faulkner, David S. Holder
    Abstract:

    Introduction Electrical Impedance Tomography (EIT) is an imaging technique where internal conductivity changes in an object are reconstructed from measurements with arrays of external electrodes. It has the potential to improve epileptogenic zone localisation as seizure activity changes local impedance in two ways. ‘Fast’ changes, ∼ 1% over millseconds, are due to the opening of ion channels during synchronised Neuronal depolarisation, and ‘slow’ changes, up to 10% over seconds, are due to cell swelling. During SEPs in anaethetised rats, EIT could image evoked activity in S1 with a resolution of 1 ms and μ m using 30 electrode epicortical arrays. EIT could offer improved resolution over the current technique of inspection of potentials with depth electrodes (SEEG) in patients undergoing presurgical seizure evaluation. EIT has the advantage that it is not sensitive to dipole orientation and coverage within a volume enclosed by electrodes is much better than for potential recording. The purpose of this study was to undertake a computer modelling study to compare fast neural EIT with SEEG and EEG inverse source modelling in subjects with epilepsy and intracranial electrodes. Methods The location and shape accuracy of reconstructed changes were assessed in 3 subjects with 48–72 depth electrode contacts and 32 scalp electrodes with EIT (1.7 kHz, 50  μ A intracranial, 250  μ A scalp), EEG inverse source modelling (ISM), and spike detection on depth electrodes (SEEG), using FEM meshes of ∼ 9 M tetrahedral elements generated from CT-MRI. EIT and inverse source reconstructions were performed on ∼ 30,000 hexahedral element meshes with zeroth order Tikhonov regularisation and noise-based image weighting. Seizure onset was simulated by 5 mm radius realistic perturbations of 1% and 10% or dipoles which produced 2 mV when 5 mm away from an electrode (5 within and 5 outside the volume enclosed by depth electrodes in each subject). Results EIT produced the best localisation. It was far superior to ISM and also provided accurate imaging for dipole sources not apparent on SEEG because of distance from the nearest electrode or tangential orientation. For perturbations placed within the depth electrodes, localisation accuracy was 5.2 ± 1.8 mm (1% change) μ V which occurred when they were >11 mm distant from the nearest electrode. For the sources in the opposite hemisphere, it was 29.6 ± 38.7 mm (1% EIT), 26.1 ± 36.2 (10% EIT), 54.0 ± 26.2 mm (ISM) and 0/15(SEEG). Conclusion In this modelling study, fast and slow neural EIT with depth electrode offers a new method for localisation of seizure onset and propagation. It employs tiny injected currents which do not damage the brain or alter cerebral function. It offers a potentially valuable additional method for presurgical epilepsy evaluation. A human clinical trial is in progress.

  • A novel method for recording Neuronal Depolarization with recording at 125-825 Hz: implications for imaging fast neural activity in the brain with electrical impedance tomography
    MED BIOL ENG COMPUT, 2011
    Co-Authors: David S. Holder
    Abstract:

    Electrical impedance tomography (EIT) is a recently developed medical imaging method which has the potential to produce images of fast Neuronal Depolarization in the brain. Previous modelling suggested that applied current needed to be below 100 Hz but the signal-to-noise ratio (SNR) recorded with scalp electrodes during evoked responses was too low to permit imaging. A novel method in which contemporaneous evoked potentials are subtracted is presented with current applied at 225 Hz to cerebral cortex during evoked activity; although the signal is smaller than at DC by about 10x, the principal noise from the EEG is reduced by about 1000x, resulting in an improved SNR. It was validated with recording of compound action potentials in crab walking leg nerve where peak changes of -0.2% at 125 and 175 Hz tallied with biophysical modelling. In recording from rat cerebral cortex during somatosensory evoked responses, peak impedance decreases of -0.07 +/- A 0.006% (mean +/- A SE) with a SNR of > 50 could be recorded at 225 Hz. This method provides a reproducible and artefact free means for recording resistance changes during Neuronal activity which could form the basis for imaging fast neural activity in the brain.

  • a method for recording resistance changes non invasively during Neuronal Depolarization with a view to imaging brain activity with electrical impedance tomography
    Journal of Neuroscience Methods, 2009
    Co-Authors: Anthony Ghosh, O Gilad, David S. Holder
    Abstract:

    Abstract Electrical impedance tomography (EIT) is a recently developed medical imaging method which has the potential to produce images of fast Neuronal Depolarization in the brain. The principle is that current remains in the extracellular space at rest but passes into the intracellular space during Depolarization through open ion channels. As current passes into the intracellular space across the capacitance of cell membranes at higher frequencies, applied current needs to be below 100 Hz. A method is presented for its measurement with subtraction of the contemporaneous evoked potentials which occur in the same frequency band. Neuronal activity is evoked by stimulation and resistance is recorded from the potentials resulting from injection of a constant current square wave at 1 Hz with amplitude less than 25% of the threshold for stimulating Neuronal activity. Potentials due to the evoked activity and the injected square wave are removed by subtraction. The method was validated with compound action potentials in crab walking leg nerve. Resistance changes of −0.85 ± 0.4% (mean ± SD) occurred which decreased from −0.97 ± 0.43% to −0.46 ± 0.16% with spacing of impedance current application electrodes from 2 to 8 mm but did not vary significantly with applied currents of 1–10 μA. These tallied with biophysical modelling, and so were consistent with a genuine physiological origin. This method appears to provide a reproducible and artefact free means for recording resistance changes during Neuronal activity which could lead to the long-term goal of imaging of fast neural activity in the brain.

  • Design of electrodes and current limits for low frequency electrical impedance tomography of the brain
    MED BIOL ENG COMPUT, 2007
    Co-Authors: David S. Holder
    Abstract:

    For the novel application of recording of resistivity changes related to Neuronal Depolarization in the brain with electrical impedance tomography, optimal recording is with applied currents below 100 Hz, which might cause neural stimulation of skin or underlying brain. The purpose of this work was to develop a method for application of low frequency currents to the scalp, which delivered the maximum current without significant stimulation of skin or underlying brain. We propose a recessed electrode design which enabled current injection with an acceptable skin sensation to be increased from 100 mu A using EEG electrodes, to 1 mA in 16 normal volunteers. The effect of current delivered to the brain was assessed with an anatomically realistic finite element model of the adult head. The modelled peak cerebral current density was 0.3 A/m(2), which was 5 to 25-fold less than the threshold for stimulation of the brain estimated from literature review.

  • design considerations and performance of a prototype system for imaging Neuronal Depolarization in the brain using direct current electrical resistance tomography
    Physiological Measurement, 1995
    Co-Authors: K G Boone, David S. Holder
    Abstract:

    The ability to image the impedance changes that accompany Neuronal Depolarization in the brain would constitute a major advance in neuroscience technology. Unfortunately, these changes are likely to be small and rapid and so difficult to measure. The impedance change at frequencies above 10 kHz, as used by conventional EIT systems, may be estimated to be about 0.1%. Modelling indicates that a much larger impedance change of about 7% may occur with DC or very-low-frequency excitation. Difficulties with this approach include a low permissible current level and high electrode impedance. We constructed a prototype system employing square wave excitation at 5 Hz to evaluate such problems. It was tested in a saline-filled tank, recording 4000 frames s-1 at a current level of 50 mu A. After averaging 100 sets of frames, the signal to noise ratio was 40-50 dB, and reciprocity errors were mostly 10-20%. Images of discrete resistivity changes of less than 10% could be obtained, but with significant systematic errors. While our prototype would not be suitable for neurophysiological imaging as it stands, it has enabled us to determine the modifications that would be required to construct a system for this application.

O Gilad - One of the best experts on this subject based on the ideXlab platform.

  • a modelling study to inform specification and optimal electrode placement for imaging of Neuronal Depolarization during visual evoked responses by electrical and magnetic detection impedance tomography
    Physiological Measurement, 2009
    Co-Authors: O Gilad, Lior Horesh, D S Holder
    Abstract:

    Electrical impedance tomography (EIT) has the potential to achieve non-invasive functional imaging of fast Neuronal activity in the human brain due to opening of ion channels during Neuronal Depolarization. Local changes of resistance in the cerebral cortex are about 1%, but the size and location of changes recorded on the scalp are unknown. The purpose of this work was to develop an anatomically realistic finite element model of the adult human head and use it to predict the amplitude and topography of changes on the scalp, and so inform specification for an in vivo measuring system. A detailed anatomically realistic finite element (FE) model of the head was produced from high resolution MRI. Simulations were performed for impedance changes in the visual cortex during evoked activity with recording of scalp potentials by electrodes or magnetic flux density by magnetoencephalography (MEG) in response to current injected with electrodes. The predicted changes were validated by recordings in saline filled tanks and with boundary voltages measured on the human scalp. Peak changes were 1.03 ± 0.75 µV (0.0039 ± 0.0034%) and 27 ± 13 fT (0.2 ± 0.5%) respectively, which yielded an estimated peak signal-to-noise ratio of about 4 for in vivo averaging over 10 min and 1 mA current injection. The largest scalp changes were over the occipital cortex. This modelling suggests, for the first time, that reproducible changes could be recorded on the scalp in vivo in single channels, although a higher SNR would be desirable for accurate image production. The findings suggest that an in vivo study is warranted in order to determine signal size but methods to improve SNR, such as prolonged averaging or other signal processing may be needed for accurate image production.

  • a method for recording resistance changes non invasively during Neuronal Depolarization with a view to imaging brain activity with electrical impedance tomography
    Journal of Neuroscience Methods, 2009
    Co-Authors: Anthony Ghosh, O Gilad, David S. Holder
    Abstract:

    Abstract Electrical impedance tomography (EIT) is a recently developed medical imaging method which has the potential to produce images of fast Neuronal Depolarization in the brain. The principle is that current remains in the extracellular space at rest but passes into the intracellular space during Depolarization through open ion channels. As current passes into the intracellular space across the capacitance of cell membranes at higher frequencies, applied current needs to be below 100 Hz. A method is presented for its measurement with subtraction of the contemporaneous evoked potentials which occur in the same frequency band. Neuronal activity is evoked by stimulation and resistance is recorded from the potentials resulting from injection of a constant current square wave at 1 Hz with amplitude less than 25% of the threshold for stimulating Neuronal activity. Potentials due to the evoked activity and the injected square wave are removed by subtraction. The method was validated with compound action potentials in crab walking leg nerve. Resistance changes of −0.85 ± 0.4% (mean ± SD) occurred which decreased from −0.97 ± 0.43% to −0.46 ± 0.16% with spacing of impedance current application electrodes from 2 to 8 mm but did not vary significantly with applied currents of 1–10 μA. These tallied with biophysical modelling, and so were consistent with a genuine physiological origin. This method appears to provide a reproducible and artefact free means for recording resistance changes during Neuronal activity which could lead to the long-term goal of imaging of fast neural activity in the brain.

  • preliminary studies in imaging Neuronal Depolarization in the brain with electrical or magnetic detection impedance tomography
    Doctoral thesis University of London., 2008
    Co-Authors: O Gilad
    Abstract:

    Electrical impedance Tomography (EIT) is a novel medical imaging method which has the potential to provide the revolutionary advance of a method to image fast neural activity non-invasively. by imaging electrical impedance changes over milliseconds which occur when Neuronal ion channels open during activity. These changes have been estimated to be c.1% locally in cerebral cortex, if measured with applied current below 100Hz. The purpose of this work was to determine if such changes could be reproducibly recorded in humans non invasive First, a novel recessed electrode was designed and tested to determine to enable a maximal current of 1mA to be applied to the scalp without causing painful skin sensation. Modelling indicated that this produced a peak current density of 0.3A/m2 in underlying cortex, which was below the threshold for stimulation. Next, the signal-to-noise ratio of impedance changes during evoked visual activity was investigated in healthy volunteers with current injected with scalp electrodes and recording of potential by scalp electrodes (Low Frequency EIT) or magnetic field by magnetoencephalography (Magnetic Detection EIT). Numerical FEM simulations predicted that resistivity changes of 1% in the primary7 visual cortex translate into scalp voltage changes of IjiV (0.004%) and external magnetic field changes of 30fT (0.2%) and were independently validated in saline filled tanks. In vivo, similar changes with a signal-to-noise ratio of 3 after averaging for 10 minutes were recorded for both methods the main noise sources were background brain activity and the current source. These studies with non-invasive scalp recording have, for the first time, demonstrated the existence of such changes when measured non-invasively. These are unfortunately too low to enable reliable imaging within a realistic recording time but support the view that such imaging could be possible in animal or human epileptic studies with electrodes placed on the brain or non-invasively following technological improvements this further work is currently in progress.

Robert J Delorenzo - One of the best experts on this subject based on the ideXlab platform.

  • activation of a novel injury induced calcium permeable channel that plays a key role in causing extended Neuronal Depolarization and initiating Neuronal death in excitotoxic Neuronal injury
    Journal of Pharmacology and Experimental Therapeutics, 2007
    Co-Authors: Laxmikant S Deshpande, David D Limbrick, Sompong Sombati, Robert J Delorenzo
    Abstract:

    Protracted elevation in intracellular calcium caused by the activation of the N-methyl-d-aspartate receptor is the main cause of glutamate excitotoxic injury in stroke. However, upon excitotoxic injury, despite the presence of calcium entry antagonists, calcium unexpectedly continues to enter the neuron, causing extended Neuronal Depolarization and culminating in Neuronal death. This phenomenon is known as the calcium paradox of Neuronal death in stroke, and it represents a major problem in developing effective therapies for the treatment of stroke. To investigate this calcium paradox and to determine the source of this unexpected calcium entry after Neuronal injury, we evaluated whether glutamate excitotoxicity activates an injury-induced calcium-permeable channel responsible for conducting a calcium current that underlies Neuronal death. We used a combination of whole-cell and single-channel patch-clamp recordings, fluorescent calcium imaging, and Neuronal cell death assays in a well characterized primary hippocampal Neuronal culture model of glutamate excitotoxicity/stroke. Here, we report activation of a novel calcium-permeable channel upon excitotoxic glutamate injury that carries calcium current even in the presence of calcium entry inhibitors. Blocking this injury-induced calcium-permeable channel for a significant time period after the initial injury is still effective in preventing calcium entry, extended Neuronal Depolarization, and delayed Neuronal death, thereby accounting for the calcium paradox. This injury-induced calcium-permeable channel represents a major source for the initial calcium entry following stroke, and it offers a new target for extending the therapeutic window for preventing Neuronal death after the initial excitotoxic (stroke) injury.

  • calcium influx constitutes the ionic basis for the maintenance of glutamate induced extended Neuronal Depolarization associated with hippocampal Neuronal death
    Cell Calcium, 2003
    Co-Authors: David D Limbrick, Sompong Sombati, Robert J Delorenzo
    Abstract:

    Abstract Excessive activation of Neuronal glutamate receptors has been implicated in the pathophysiology of stroke, epilepsy, and traumatic brain injury. Previously, it has been demonstrated that excitotoxic glutamate exposure results in the induction of an extended Neuronal Depolarization (END), as well as protracted elevations in free intracellular calcium ([Ca2+]i). Both END and the prolonged [Ca2+]i elevations were shown to correlate with subsequent Neuronal death. In the current study, we used whole-cell current-clamp electrophysiology and fura-ff Ca2+ imaging to determine the electrophysiological basis of END. We found that removal of extracellular Ca2+ but not Na+ in the post-glutamate period resulted in complete reversal of END, allowing neurons to rapidly repolarize to their initial resting membrane potential (RMP). In addition, removal of extracellular Ca2+ was sufficient to eliminate the protracted [Ca2+]i elevations induced by excitotoxic glutamate exposure. To investigate the mechanism through which extracellular Ca2+ was effecting these changes, pharmacolgical antagonists of well-characterized routes of Ca2+ entry were tested for their effects on END. Antagonists of glutamate receptors and voltage-gated Ca2+ channels (VGCCs) had no significant effect on the membrane potential of neurons in END. Likewise, inhibitors of the Na+/Ca2+ exchange (NCX) were ineffective. In contrast, addition of 500 μM ZnCl2 or 100 μM GdCl3 to control extracellular medium (containing normal levels of exctracellular Ca2+) in the post-glutamate period resulted in rapid and complete reversal of END. Addition of 1 mM CdCl2 to control medium had only modest effects on END. These data provide the first direct evidence that END induced by excitotoxic glutamate exposure is caused by an influx of extracellular Ca2+ and demonstrate that the previously irreversible condition of END can be reversed by removing extracellular Ca2+. In addition, understanding the electrophysiological basis of this novel Ca2+-induced extended Depolarization may provide an insight into the pathophysiology of stroke, traumatic brain injury, and other forms of Neuronal injury.

  • Induction of spontaneous recurrent epileptiform discharges causes long-term changes in intracellular calcium homeostatic mechanisms.
    Cell Calcium, 2000
    Co-Authors: David D Limbrick, Azhar Rafiq, Robert J Delorenzo
    Abstract:

    Calcium and calcium-dependent systems have been long implicated in the induction of epilepsy. We have previously observed that intracellular calcium ([Ca2+]i) levels remain elevated in cells undergoing epileptogenesis in the hippocampal Neuronal culture (HNC) model. In this study, we employed the hippocampal Neuronal culture (HNC) model of in vitro ‘epilepsy’ which produces spontaneous recurrent epileptiform discharges (SREDs) for the life of the neurons in culture to investigate alterations in [Ca2+]ihomeostatic mechanisms that may be associated with the ‘epileptic’ phenotype. [Ca2+]iimaging fluorescence microscopy was performed on control and ‘epileptic’ neurons with two different fluorescent dyes ranging from high to low affinities for [Ca2+]i. We measured baseline [Ca2+]ilevels and the ability to restore resting [Ca2+]ilevels after a brief 2-min exposure to the excitatory amino acid glutamate in control neurons and neurons with SREDs. Neurons manifesting SREDs had statistically significantly higher baseline [Ca2+]ilevels that persisted for the life of the culture. In addition, the ‘epileptic’ phenotype was associated with an inability to rapidly restore [Ca2+]ilevels to baseline following a glutamate induced [Ca2+]iload. The use of the low affinity dye Fura-FF demonstrated that the difference in restoring baseline [Ca2+]ilevels was not due to saturation of the high affinity dye Indo-1, which was utilized for evaluating the [Ca2+]ikinetics at lower [Ca2+]ilevels. Peak [Ca2+]ilevels in response to glutamate were the same in both ‘epileptic’ and control neurons. While [Ca2+]ilevels recovered in approximately 30 min in control cells, it took more than 90 min to reach baseline levels in cells manifesting SREDs. Alterations of [Ca2+]ihomeostatic mechanisms observed with the ‘epileptic’ phenotype were shown to be independent of the presence of continuous SREDs and persisted for the life of the neurons in culture. Epileptogenesis was shown not to affect the degree or duration of glutamate induced Neuronal Depolarization in comparing control and ‘epileptic’ neurons. The results indicate that epileptogenesis in this in vitro model produced long-lasting alterations in [Ca2+]iregulation that may underlie the ‘epileptic’ phenotype and contribute to the persistent neuroplasticity changes associated with epilepsy.

  • electrophysiology of glutamate neurotoxicity in vitro induction of a calcium dependent extended Neuronal Depolarization
    Journal of Neurophysiology, 1992
    Co-Authors: Douglas A Coulter, Sompong Sombati, Robert J Delorenzo
    Abstract:

    1. Physiological responses of hippocampal pyramidal neurons in primary culture to prolonged glutamate (GLU) exposure (500 microM in all experiments) were studied with the use of patch electrodes and whole-cell current-clamp recording techniques. In some experiments, perforated patch recordings were employed with electrodes containing the pore-forming antibiotic nystatin. 2. After washout of GLU after a 10-min exposure, pyramidal neurons remained depolarized by greater than or equal to 20 mV from rest for the duration of the recording (30 min to less than 4 h). This Depolarization was accompanied by a 57.8% increase in membrane conductance and was termed an extended Neuronal Depolarization (END). The percentage of neurons in which END was induced varied with the duration of GLU exposure, with a 4-, 6-, 8-, 10-, and 20-min GLU exposure eliciting END in 12.5, 41.7, 81.8, 100, and 100% of neurons. END induction appeared to be an all-or-none phenomenon, because END levels did not differ when compared across GLU exposure times. 3. During the END, cells retained both the ability to fire action potentials and the ability to respond to GLU, appeared viable when examined anatomically, and still excluded vital dyes. This supports the conclusion that END is not a nonspecific consequence of cell death. Rather, END is a discrete physiological process triggered by prolonged GLU exposure. The results raise questions concerning the reversibility of END induction, i.e., can neurons be "rescued" once END is induced, or will these cells inevitably go on to die? 4. END induction was dependent on a rise in intracellular free calcium ([Ca]i). END was prevented by strong buffering of [Ca]i or by substitution of external Ba2+ for Ca2+. However, substitution of Mn2+ for Ca2+ still permitted END induction. In cells recorded with the perforated-patch technique, maintaining normal [Ca]i levels, END could be induced, but less readily than under unbuffered [Ca]i conditions. 5. END could not be induced by a 10- to 20-min current-clamp Depolarization to 0 mV, nor by 10-min GLU application while the membrane potential was voltage clamped at rest in a solution containing 1 mM Mg2+. In addition, END induction by GLU could be blocked by application of MK-801 (10-30 microM) but not 6-cyano-7-nitroquinoxaline-2,3-dione [CNQX (100-200 microM)]. 6. The dependence of both delayed Neuronal cell death and END induction on GLU exposure duration were similar.(ABSTRACT TRUNCATED AT 400 WORDS)

  • neurotoxic activation of glutamate receptors induces an extended Neuronal Depolarization in cultured hippocampal neurons
    Brain Research, 1991
    Co-Authors: Sompong Sombati, Douglas A Coulter, Robert J Delorenzo
    Abstract:

    Abstract Intracellular recording revealed that cytotoxic activation of excitatory amino acid receptors by glutamate or N- methyl- d -aspartate (NMDA) elicited an extended Neuronal Depolarization (END) of at least 5 h duration following washout of glutamate in hippocampal neurons in culture. During END, cell were still responsive to glutamate, and still able to fire sodium spikes. END induction could be blocked by concurrent application of d -2-amino-5-phosphonovalerate (APV) or MK-801, but not 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), during the glutamate exposure. The induction of END by excitotoxic glutamate receptor activation may play a role in the pathophysiology of glutamate toxicity.

Rowan, Edward G. - One of the best experts on this subject based on the ideXlab platform.

  • Scorpion venom increases acetylcholine release by prolonging the duration of somatic nerve action potentials
    Reino Unido, 2020
    Co-Authors: Collaço, Rita De Cássia O., Hyslop Stephen, Antunes Edson, Dorce, Valquiria A. C., Rowan, Edward G.
    Abstract:

    Scorpionism is frequently accompanied by a massive release of catecholamines and acetylcholine from peripheral nerves caused by neurotoxic peptides present in these venoms, which have high specificity and affinity for ion channels. Tityus bahiensis is the second most medically important scorpion species in Brazil but, despite this, its venom remains scarcely studied, especially with regard to its pharmacology on the peripheral (somatic and autonomic) nervous system. Here, we evaluated the activity of T. bahiensis venom on somatic neurotransmission using myographic (chick and mouse neuromuscular preparations), electrophysiological (MEPP, EPP, resting membrane potentials, perineural waveforms, compound action potentials) and calcium imaging (on DRG neurons and muscle fibres) techniques. Our results show that the major toxic effects of T. bahiensis venom on neuromuscular function are presynaptically driven by the increase in evoked and spontaneous neurotransmitter release. Low venom concentrations prolong the axonal action potential, leading to a longer Depolarization of the nerve terminals that enhances neurotransmitter release and facilitates nerve-evoked muscle contraction. The venom also stimulates the spontaneous release of neurotransmitters, probably through partial Neuronal Depolarization that allows calcium influx. Higher venom concentrations block the generation of action potentials and resulting muscle twitches. These effects of the venom were reversed by low concentrations of TTX, indicating voltage-gated sodium channels as the primary target of the venom toxins. These results suggest that the major neuromuscular toxicity of T. bahiensis venom is probably mediated mainly by alpha- and beta-toxins interacting with presynaptic TTX-sensitive ion channels on both axons and nerve terminals1534152CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP142460/2014-1; 310547/2014-82016/11319-6; 2016/23829-9; 17/15175-

  • Scorpion venom increases acetylcholine release by prolonging the duration of somatic nerve action potentials
    'Elsevier BV', 2019
    Co-Authors: Collaço, Rita De Cássia O., Hyslop Stephen, Dorce, Valquíria A.c., Antunes Edson, Rowan, Edward G.
    Abstract:

    Scorpionism is frequently accompanied by a massive release of catecholamines and acetylcholine from peripheral nerves caused by neurotoxic peptides present in these venoms, which have high specificity and affinity for ion channels. Tityus bahiensis is the second most medically important scorpion species in Brazil but, despite this, its venom remains scarcely studied, especially with regard to its pharmacology on the peripheral (somatic and autonomic) nervous system. Here, we evaluated the activity of T. bahiensis venom on somatic neurotransmission using myographic (chick and mouse neuromuscular preparations), electrophysiological (MEPP, EPP, resting membrane potentials, perineural waveforms, compound action potentials) and calcium imaging (on DRG neurons and muscle fibres) techniques. Our results show that the major toxic effects of T. bahiensis venom on neuromuscular function are presynaptically driven by the increase in evoked and spontaneous neurotransmitter release. Low venom concentrations prolong the axonal action potential, leading to a longer Depolarization of the nerve terminals that enhances neurotransmitter release and facilitates nerve-evoked muscle contraction. The venom also stimulates the spontaneous release of neurotransmitters, probably through partial Neuronal Depolarization that allows calcium influx. Higher venom concentrations block the generation of action potentials and resulting muscle twitches. These effects of the venom were reversed by low concentrations of TTX, indicating voltage-gated sodium channels as the primary target of the venom toxins. These results suggest that the major neuromuscular toxicity of T. bahiensis venom is probably mediated mainly by α- and β-toxins interacting with presynaptic TTX-sensitive ion channels on both axons and nerve terminals

Herman Wolosker - One of the best experts on this subject based on the ideXlab platform.

  • Neuronal release of d-serine: a physiological pathway controlling extracellular d-serine concentration
    The FASEB Journal, 2010
    Co-Authors: Dina Rosenberg, Maria Shleper, Elena Kartvelishvily, Chanda Ciriacks Klinker, Michael T. Bowser, Herman Wolosker
    Abstract:

    d-Serine is thought to be a glia-derived transmitter that activates N-methyl d-aspartate receptors (NMDARs) in the brain. Here, we investigate the pathways for d-serine release using primary cultures, brain slices, and in vivo microdialysis. In contrast with the notion that d-serine is exclusively released from astrocytes, we found that d-serine is released by Neuronal Depolarization both in vitro and in vivo. Veratridine (50 μM) or Depolarization by 40 mM KCl elicits a significant release of endogenous d-serine from primary Neuronal cultures. Controls with astrocyte cultures indicate that glial cells are insensitive to veratridine, but release d-serine mainly by the opening of volume-regulated anion channels. In cortical slices perfused with veratridine, endogenous d-serine release is 10-fold higher than glutamate receptor-evoked release. Release of d-serine from slices does not require internal or external Ca2+, suggesting a nonvesicular release mechanism. To confirm the Neuronal origin of d-serine, we selectively loaded neurons in cortical slices with d-[3H]serine or applied d-alanine, which specifically releases d-serine from neurons. Depolarization with veratridine promotes d-serine release in vivo monitored by high temporal resolution microdialysis of the striatum. Our data indicate that the Neuronal pool of d-serine plays a major role in d-serine dynamics, with implications for the regulation of NMDAR transmission. Rosenberg, D., Kartvelishvily, E., Shleper, M., Klinker, C. M. C., Bowser, M. T., Wolosker, H. Neuronal release of d-serine: a physiological pathway controlling extracellular d-serine concentration.