Alon Korngreen | Bar-Ilan University (original) (raw)

Papers by Alon Korngreen

The Journal of physiology, Jan 15, 1996

1. Simultaneous measurements of average intracellular calcium concentration ([Ca2+]i) and ciliary... more 1. Simultaneous measurements of average intracellular calcium concentration ([Ca2+]i) and ciliary beat frequency (CBF) were carried out on ciliated rabbit tracheal cells in order to determine quantitatively the role of calcium in the regulation of mucus-transporting cilia. 2. Extracellular ATP caused a rapid increase in both [Ca2+]i and CBF in the 0.1-1000 microM concentration range. The rise in [Ca2+]i levelled off to an elevated [Ca2+]i plateau while the cilia remained in a high activation state. The magnitude of the rise in [Ca2+]i and CBF as well as the value of the elevated [Ca2+]i plateau and the value of the sustained CBF were dependent on the concentration of ATP in the solution. 3. No correlation was found between the mean values of [Ca2+]i and CBF at rest but a sigmoidal relationship was found to exist between the maximal rises of these parameters following excitation with extracellular ATP. This sigmoidal correlation incorporated the experiments where [Ca2+]i rise was ind...

Frontiers in Cellular Neuroscience, 2014

Although transcranial magnetic stimulation (TMS) is a popular tool for both basic research and cl... more Although transcranial magnetic stimulation (TMS) is a popular tool for both basic research and clinical applications, its actions on nerve cells are only partially understood. We have previously predicted, using compartmental modeling, that magnetic stimulation of central nervous system neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. The simulations also predict that neurons with low current threshold are more susceptible to magnetic stimulation. Here we tested these theoretical predictions by combining in vitro patch-clamp recordings from rat brain slices with magnetic stimulation and compartmental modeling. In agreement with the modeling, our recordings demonstrate the dependence of magnetic stimulation-triggered action potentials on the type and state of the neuron and its orientation within the magnetic field. Our results suggest that the observed effects of TMS are deeply rooted in the biophysical properties of single neurons in the central nervous system and provide a framework both for interpreting existing TMS data and developing new simulation-based tools and therapies.

Cell Motility and the Cytoskeleton, 1998

In the present work we report that increasing the viscosity of the medium caused not only a decre... more In the present work we report that increasing the viscosity of the medium caused not only a decrease in the ciliary beat frequency but also changes in the metachrony and correlation between cilia. The study was performed using double and triple simultaneous photoelectric measurements on cultured ciliary cells from the frog esophagus in the viscosity range of 1-2,000 cp. We observed that increasing the viscosity intensified the fluctuations in all the measured parameters. Ciliary beat frequency decreased moderately. Even at quite high viscosities (circa 2000 cp.), cilia were still active with beating frequencies of 3-5 Hz. In addition, the degree of correlation between cilia parallel to the effective stroke direction (ESD) decreased, while that perpendicular to the ESD at a low range of viscosities remained unchanged and even increased at high viscosities. Medium viscosities in the range of 30-1,500 cp. altered the metachronal wave properties of cultured frog esophagus. The metachronal wavelength increased by up to 50%, and the wave direction changed towards more orthoplectic type of coordination. According to our recently suggested model [Gheber and Priel, 1990: Cell Motil. Cytoskeleton 16:167-181], these effects can be explained by a decrease in the temporal asymmetry of the ciliary beat. Since similar results were observed in water propelling cilia of Paramecium subjected to medium viscosity ranges of up to 40 cp. [Machemer, 1972: J. Exp. Biol. 57:239-259], we conclude that hydrodynamic interactions govern the metachronal wave properties of both mucus and water propelling cilia, though mucus propelling cilia, with their better adaptation to increased load, are affected at much higher viscosities than water propelling cilia.

Frontiers in Systems Neuroscience, 2014

Journal of Neuroscience, 2013

The firing patterns of neurons in the globus pallidus (GP) are affected by two major sources of G... more The firing patterns of neurons in the globus pallidus (GP) are affected by two major sources of GABAergic inhibition: striatal afferents and local axon collaterals. Local GABAergic GP-GP synapses display short-term depression (STD) and very sparse connectivity. At the high presynaptic firing rates typical in the GP, one would expect this STD to be complete, practically cancelling the postsynaptic impact of the synapse. To investigate the apparent paradox of a synapse not affecting its postsynaptic neuron, we performed dual whole-cell recordings in acute brain slices from rats and recorded, for the first time, unitary IPSPs from a GP-GP GABAergic connection. We show that at high presynaptic firing rates the unitary connection continuously modulates the postsynaptic firing rate through a combination of large chloride driving force, unitary IPSP summation, and incomplete synaptic depression. Our findings indicate that, despite substantial STD and sparse connectivity, local GABAergic axon collaterals in the GP may echo the changes in presynaptic firing frequency across postsynaptic targets.

PLoS ONE, 2009

KCNQ2/KCNQ3 channels are the molecular correlates of the neuronal M-channels, which play a major ... more KCNQ2/KCNQ3 channels are the molecular correlates of the neuronal M-channels, which play a major role in the control of neuronal excitability. Notably, they differ from homomeric KCNQ2 channels in their distribution pattern within neurons, with unique expression of KCNQ2 in axons and nerve terminals. Here, combined reciprocal coimmunoprecipitation and twoelectrode voltage clamp analyses in Xenopus oocytes revealed a strong association of syntaxin 1A, a major component of the exocytotic SNARE complex, with KCNQ2 homomeric channels resulting in a ,2-fold reduction in macroscopic conductance and ,2-fold slower activation kinetics. Remarkably, the interaction of KCNQ2/Q3 heteromeric channels with syntaxin 1A was significantly weaker and KCNQ3 homomeric channels were practically resistant to syntaxin 1A. Analysis of different KCNQ2 and KCNQ3 chimeras and deletion mutants combined with in-vitro binding analysis pinpointed a crucial Cterminal syntaxin 1A-association domain in KCNQ2. Pull-down and coimmunoprecipitation analyses in hippocampal and cortical synaptosomes demonstrated a physical interaction of brain KCNQ2 with syntaxin 1A, and confocal immunofluorescence microscopy showed high colocalization of KCNQ2 and syntaxin 1A at presynaptic varicosities. The selective interaction of syntaxin 1A with KCNQ2, combined with a numerical simulation of syntaxin 1A's impact in a firingneuron model, suggest that syntaxin 1A's interaction is targeted at regulating KCNQ2 channels to fine-tune presynaptic transmitter release, without interfering with the function of KCNQ2/3 channels in neuronal firing frequency adaptation.

PLoS Computational Biology, 2011

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generate... more Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fiber's diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.

Neuroscience Letters, 2011

Repetitive transcranial magnetic stimulation (rTMS) is a standard tool in neuroscience research a... more Repetitive transcranial magnetic stimulation (rTMS) is a standard tool in neuroscience research and therapy. Here we study one rTMS property that has not received adequate attention, the interaction of subthreshold intensity stimulation and low frequencies. We applied 1 Hz rTMS over the motor cortex at three intensities, 40%, 80% and 100% of the resting motor threshold (rMT), and measured cortical excitability before and after the stimulation sessions. When comparing motor evoked potential (MEP) measured from the abductor pollicis brevis (APB) muscle before and after rTMS stimulation, we found that low intensity (40% MT) stimulation significantly decreased MEP magnitude, some smaller (nonsignificant) inhibition was found for the 80% MT intensity and increased MEP was found for the high intensity (100% MT) stimulation. Our results indicate that when explaining the input-output relationship of motor cortex induced activation as an intensity-dependent function, there might be a need to split it into separate functions associated with separate processes mediated by different cell types such as interneurons, pyramidal neurons and others.

Neurobiology of Disease, 2012

Parkinsonism is associated with major changes in neuronal activity throughout the cortico-basal g... more Parkinsonism is associated with major changes in neuronal activity throughout the cortico-basal ganglia loop. Current measures quantify changes in baseline neuronal and network activity but do not capture alterations in information propagation throughout the system. Here, we applied a novel non-invasive magnetic stimulation approach using a custom-made mini-coil that enabled us to study transmission of neuronal activity throughout the cortico-basal ganglia loop in both normal and parkinsonian primates. By magnetically perturbing cortical activity while simultaneously recording neuronal responses along the cortico-basal ganglia loop, we were able to directly investigate modifications in descending cortical activity transmission. We found that in both the normal and parkinsonian states, cortical neurons displayed similar multi-phase firing rate modulations in response to magnetic stimulation. However, in the basal ganglia, large synaptically driven stereotypic neuronal modulation was present in the parkinsonian state that was mostly absent in the normal state. The stimulation-induced neuronal activity pattern highlights the change in information propagation along the cortico-basal ganglia loop. Our findings thus point to the role of abnormal dynamic activity transmission rather than changes in baseline activity as a major component in parkinsonian pathophysiology. Moreover, our results hint that the application of transcranial magnetic stimulation (TMS) in human patients of different disorders may result in different neuronal effects than the one induced in normal subjects.

Journal of Neurophysiology, 2010

Frontiers in Systems Neuroscience, 2011

Electrical stimulation in the globus pallidus (GP) leads to complex modulations of neuronal activ... more Electrical stimulation in the globus pallidus (GP) leads to complex modulations of neuronal activity in the stimulated nucleus. Multiple in vivo studies have demonstrated the modulation of both firing rates and patterns during and immediately following the GP stimulation. Previous in vitro studies, together with computational studies, have suggested the involvement of short-term synaptic plasticity (STP) during the stimulation. The aim of the current study was to explore in vitro the effects of STP on neuronal activity of GP neurons during local repetitive stimulation. We recorded synaptic potentials and assessed the modulations of spontaneous firing in a postsynaptic neuron in acute brain slices via a whole-cell pipette. Low-frequency repetitive stimulation locked the firing of the neuron to the stimulus. However, high-frequency repetitive stimulation in the GP generated a biphasic modulation of the firing frequency consisting of inhibitory and excitatory phases. Using blockers of synaptic transmission, we show that GABAergic synapses mediated the inhibitory and glutamatergic synapses the excitatory part of the response. Furthermore, we report that at high stimulation frequencies both types of synapses undergo short-term depression leading to a time dependent modulation of the neuronal firing. These findings indicate that STP modulates the dynamic responses of pallidal activity during electrical stimulation, and may contribute to a better understanding of the mechanism underlying deep brain stimulation like protocols.

Brain Research, 2008

Human embryonic stem cells (hESC) have been directed to differentiate into CNS cells with clinica... more Human embryonic stem cells (hESC) have been directed to differentiate into CNS cells with clinical importance. However, for study of development and regeneration of the human PNS, and peripheral neuropathies, it would be useful to have a source of human PNS derivatives. We have demonstrated that peripheral sensory neuron-like cells (PSN) can also be derived from hESC via neural crest-like (NC) intermediates, and from neural progenitors induced from hESC using noggin. Here we report the generation of higher purity PSN from passagable neurospheres (NSP) induced by murine PA6 stromal cells. hESC were cultured with PA6, and colonies that developed a specific morphology were cut from the plates.

Biophysical Journal, 1997

In many electrically nonexcitable cells, the release of calcium from internal stores is followed ... more In many electrically nonexcitable cells, the release of calcium from internal stores is followed by a much slower phase in which the intracellular calcium concentration decreases gradually to a sustained value higher than the concentration before stimulation. This elevated calcium plateau has been shown to be the result of calcium influx. The model presented in this work describes a system consisting of a cytoplasmic calcium store and a plasma membrane calcium channel, both excitable by a membrane receptor; a fast cytoplasmic calcium buffer; and calcium pumps in both the calcium store and cellular membranes. Inherent difficulties in the numerical evaluation of the model, caused by very large calcium fluxes across the store membrane, were overcome by analytically separating the fast processes of calcium release from the slower processes of calcium cycling across the plasma membrane. This enabled the simulation of realistic biphasic calcium transients similar to those observed experimentally. The model predicted 1) a strong correlation between the rate of calcium cycling across the plasma membrane and the rate of calcium decay; and 2) a dependence on the level of cell excitation of the maximum rise in cytoplasmic calcium concentration, the level of the elevated calcium plateau, and the rate of calcium decay. Using the model, we simulated the washout of agonist from the bathing solution and the depletion of the calcium store by a pharmacological agent (such as thapsigargin) under several experimental conditions.

Biophysical Journal, 1996

To examine the role of membrane dynamics in transmembrane signal transduction, we studied changes... more To examine the role of membrane dynamics in transmembrane signal transduction, we studied changes in membrane fluidity in mucociliary tissues from frog palate and esophagus epithelia stimulated by extracellular ATP. Micromolar concentrations of ATP induced strong changes in fluorescence polarization, possibly indicating membrane fluidization. This effect was dosage dependent, reaching a maximum at 1 0-,uM ATP. It was dependent on the presence of extracellular Ca2" (or Mg2"), though it was insensitive to inhibitors of voltage-gated calcium channels. It was inhibited by thapsigargin and by ionomycin (at low extracellular Ca2`concentration), both of which deplete Ca2+ stores. It was inhibited by the calciumactivated potassium channel inhibitors quinidine, charybdotoxin, and apamine and was reduced considerably by replacement of extracellular Na+ with K+. Hyperpolarization, or depolarization, of the mucociliary membrane induced membrane fluidization. The degree of membrane fluidization depended on the degree of hyperpolarization or depolarization of the ciliary membrane potential and was considerably lower than the effect induced by extracellular ATP. These results indicate that appreciable membrane fluidization induced by extracellular ATP depends both on an increase in intracellular Ca2 , mainly from its internal stores, and on hyperpolarization of the membrane. Calcium-dependent potassium channels couple the two effects. In light of recent results on the enhancement of ciliary beat frequency, it would appear that extracellular ATP-induced changes both in ciliary beat frequency and in membrane fluidity are triggered by similar signal transduction pathways.

Biophysical Journal, 1994

A novel system for measuring, simultaneously, ciliary beating and intracellular free calcium is p... more A novel system for measuring, simultaneously, ciliary beating and intracellular free calcium is presented. The advantages and dynamic nature of the system are demonstrated by measuring the effects of the calcium ionophore lonomycin and of extracellular ATP on ciliated rabbit trachea. The results are discussed with regard to the ciliary and calcium stimulation.

Scientific publication is adapting, like other facets of everyday life, to the Internet. The rapi... more Scientific publication is adapting, like other facets of everyday life, to the Internet. The rapid rise in online articles has pitted the rigid rules of scientific publication against the extreme flexibility of the Internet. In some cases these two opposing forces act in synergy while in others strange chimeras have emerged. One of these derives from the ability to make supplementary material available online as a complement to manuscripts. This comes in many forms ranging from traditional text, tables and figures, to newer multimedia formats ...

Pyramidal neurones of layer 5 in the neocortex are primary output cells of the cortex (White, 198... more Pyramidal neurones of layer 5 in the neocortex are primary output cells of the cortex (White, 1989). They have an elaborate dendritic tree that contains several types of voltagegated channels such as Na¤, K¤ and Ca¥ channels. These channels take part in the spread of both subthreshold