Developmental upregulation of presynaptic NCKX underlies the decrease of mitochondria-dependent posttetanic potentiation at the rat calyx of Held synapse

2013 ◽  
Vol 109 (7) ◽  
pp. 1724-1734 ◽  
Author(s):  
Jae Sung Lee ◽  
Myoung-Hwan Kim ◽  
Won-Kyung Ho ◽  
Suk-Ho Lee
Keyword(s):  
High Frequency ◽  
Developmental Change ◽  
High Frequency Stimulation ◽  
Posttetanic Potentiation ◽  
Calyx Of Held ◽  
Low Concentration ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

The sensitivity of posttetanic potentiation (PTP) to high-frequency stimulation (HFS) steeply decays during the first 2 postnatal weeks. We investigated the underlying mechanisms for the developmental change of PTP induced by HFS (100 Hz, 2 s) at postnatal days 4–6 and 9–11 at the rat calyx of Held synapse. Low-concentration tetraphenylphosphonium (2 μM), an inhibitor of mitochondrial Na+/Ca2+ exchanger, suppressed the amount of posttetanic residual Ca2+ and PTP to a larger extent at the immature calyx synapse, indicating a developmental reduction of mitochondrial contribution to PTP. The higher amount of mitochondrial Ca2+ uptake during HFS and consequent posttetanic residual Ca2+ at the immature calyx of Held was associated with higher peak of HFS-induced Ca2+ transients, most likely because the mitochondrial Ca2+ uptake during HFS was supralinearly dependent on the presynaptic resting Ca2+ level. Probing into the contribution of Na+/Ca2+ exchangers to Ca2+ clearance, we found a specific upregulation of the K+-dependent Na+/Ca2+ exchanger (NCKX) activity in the mature calyx of Held. We conclude that the upregulation of NCKX limits the Ca2+ buildup and inhibits mitochondrial Ca2+ uptake during HFS, which in turn results in the reduction of posttetanic residual Ca2+ and PTP at the mature calyx of Held synapse.

scholarly journals Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer A. Sheth ◽  
Nuri F. Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

AbstractDespite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130–180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

Electroceutically induced subthalamic high frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's Disease

2020 ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer Sheth ◽  
Nuri Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

Abstract Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by therapeutic and non-therapeutic electrical stimulation of the subthalamic nucleus (STN) in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20Hz) stimulation, the HFOs were induced only with therapeutic frequencies and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA.We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

Changes in the Readily Releasable Pool of Transmitter and in Efficacy of Release Induced by High-Frequency Firing at Aplysia Sensorimotor Synapses in Culture

2004 ◽  
Vol 91 (4) ◽  
pp. 1500-1509 ◽  
Author(s):  
Yali Zhao ◽  
Marc Klein
Keyword(s):  
Motor Neuron ◽  
High Frequency ◽  
Transmitter Release ◽  
Action Potentials ◽  
High Frequency Stimulation ◽  
Hypertonic Solution ◽  
Posttetanic Potentiation ◽  
Releasable Pool ◽  
Readily Releasable Pool ◽  
Frequency Stimulation

Synaptic transmission at the sensory neuron-motor neuron synapses of Aplysia, like transmission at many synapses of both vertebrates and invertebrates, is increased after a short burst of high-frequency stimulation (HFS), a phenomenon known as posttetanic potentiation (PTP). PTP is generally attributable to an increase in transmitter release from presynaptic neurons. We investigated whether changes in the readily releasable pool of transmitter (RRP) contribute to the potentiation that follows HFS. We compared the changes in excitatory postsynaptic potentials (EPSPs) evoked with action potentials to changes in the RRP as estimated from the asynchronous transmitter release elicited by a hypertonic solution. The changes in the EPSP were correlated with changes in the RRP, but the changes matched quantitatively only at connections whose initial synaptic strength was greater than the median for all experiments. At weaker connections, the increase in the RRP was insufficient to account for PTP. Weaker connections initially released a smaller fraction of the RRP with each EPSP than stronger ones, and this fraction increased at weaker connections after HFS. Moreover, the initial transmitter release in response to the hypertonic solution was accelerated after HFS, indicating that the increase in the efficacy of release was not restricted to excitation-secretion coupling. Modulation of the RRP and of the efficacy of release thus both contribute to the enhancement of transmitter release by HFS.

EPSP Amplitude Modulation at the Rat Ia-Alpha Motoneuron Synapse: Effects of GABAB Receptor Agonists and Antagonists

1998 ◽  
Vol 79 (1) ◽  
pp. 181-189 ◽  
Author(s):  
Kavita R. Peshori ◽  
William F. Collins ◽  
Lorne M. Mendell
Keyword(s):  
Amplitude Modulation ◽  
High Frequency ◽  
Low Frequency ◽  
High Frequency Stimulation ◽  
Posttetanic Potentiation ◽  
Epsp Amplitude ◽  
Frequency Stimulation ◽  
The Relationship ◽  
Receptor Agonists And Antagonists ◽  
Cgp 35348

Peshori, Kavita R., William F. Collins III, and Lorne M. Mendell. EPSP amplitude modulation at the rat Ia-alpha motoneuron synapse: effects of GABAB receptor agonists and antagonists. J. Neurophysiol. 79: 181–189, 1998. The object of this study was to examine the relationship between excitatory postsynaptic potential (EPSP) amplitude, posttetanic potentiation, and EPSP amplitude modulation at synapses made by group Ia afferents on motoneurons in the rat. These relationships were evaluated in cells in untreated rats and in cells in rats treated with the γ-aminobutyric acid-B (GABAB) receptor agonist baclofen and antagonist CGP-35348, which were used to manipulate Ca2+ entry into presynaptic terminals and consequently probability of transmitter release from them. There was no evidence for postsynaptic action of these drugs from measurement of their effects on motoneuron properties. During high-frequency stimulation (32 shock bursts at 167 Hz), EPSP amplitude either decreased (negative modulation) or increased (positive modulation) in response to successive stimuli at different connections. In untreated rats this frequency-dependent amplitude modulation behavior was inversely but weakly correlated with EPSP amplitude measured at low frequency. Intravenous (iv) administration of the GABAB agonist, baclofen, produced a marked and progressive decrease in EPSP amplitude measured at low frequency coincident with a change in frequency-dependent EPSP amplitude modulation toward more positive values (synaptic facilitation). In contrast, an increase in EPSP amplitude occurred after iv administration of the GABAB antagonist CGP-35348 that was accompanied by a negative shift in EPSP amplitude modulation during high-frequency stimulation. The negative shift in EPSP amplitude modulation (synaptic depression) after CGP-35348 application was much smaller than the positive shift induced by baclofen when normalized to the change in EPSP amplitude. Posttetanic potentiation decreased after baclofen but did not increase after CGP-35348. The relationship between modulation and EPSP amplitude was much steeper after GABAB receptor manipulation in either direction than that observed in the population of motoneurons in untreated preparations. This suggests that in the rat differences in probability of release play at most a small role in determining EPSP amplitude across the motoneuron pool.

Cellular mechanisms of fatigue in skeletal muscle

1991 ◽  
Vol 261 (2) ◽  
pp. C195-C209 ◽  
Author(s):  
H. Westerblad ◽  
J. A. Lee ◽  
J. Lannergren ◽  
D. G. Allen
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
High Frequency ◽  
Force Production ◽  
High Frequency Stimulation ◽  
Tetanic Stimulation ◽  
Cellular Mechanisms ◽  
Frequency Stimulation ◽  
T Tubules ◽  
Underlying Mechanisms

Prolonged activation of skeletal muscle leads to a decline of force production known as fatigue. In this review we outline the ionic and metabolic changes that occur in muscle during prolonged activity and focus on how these changes might lead to reduced force. We discuss two distinct types of fatigue: fatigue due to continuous high-frequency stimulation and fatigue due to repeated tetanic stimulation. The causes of force decline are considered under three categories: 1) reduced Ca2+ release from the sarcoplasmic reticulum, 2) reduced myofibrillar Ca2+ sensitivity, and 3) reduced maximum Ca(2+)-activated tension. Reduced Ca2+ release can be due to impaired action potential propagation in the T tubules, and this is a principal cause of the tension decline with continuous tetanic stimulation. Another type of failing Ca2+ release, which is homogeneous across the fibers, is prominent with repeated tetanic stimulation; the underlying mechanisms of this reduction are not fully understood, although several possibilities emerge. Changes in intracellular metabolites, particularly increased concentration of Pi and reduced pH, lead to reduced Ca2+ sensitivity and reduced maximum tension, which make an important contribution to the force decline, especially with repeated tetanic stimulation.

scholarly journals Cholinergic mechanisms of high-frequency stimulation in entopeduncular nucleus

2016 ◽  
Vol 115 (1) ◽  
pp. 60-67 ◽  
Author(s):  
Feng Luo ◽  
Zelma H. T. Kiss
Keyword(s):  
High Frequency ◽  
Receptor Activation ◽  
Inhibitory Synapses ◽  
High Frequency Stimulation ◽  
Entopeduncular Nucleus ◽  
Cellular Mechanisms ◽  
Cholinergic Mechanism ◽  
Whole Cell Patch Clamp ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

Chronic, high-frequency (>100 Hz) electrical stimulation, known as deep brain stimulation (DBS), of the internal segment of the globus pallidus (GPi) is a highly effective therapy for Parkinson's disease (PD) and dystonia. Despite some understanding of how it works acutely in PD models, there remain questions about its mechanisms of action. Several hypotheses have been proposed, such as depolarization blockade, activation of inhibitory synapses, depletion of neurotransmitters, and/or disruption/alteration of network oscillations. In this study we investigated the cellular mechanisms of high-frequency stimulation (HFS) in entopeduncular nucleus (EP; rat equivalent of GPi) neurons using whole cell patch-clamp recordings. We found that HFS applied inside the EP nucleus induced a prolonged afterdepolarization that was dependent on stimulation frequency, pulse duration, and current amplitude. The high frequencies (>100 Hz) and pulse widths (>0.15 ms) used clinically for dystonia DBS could reliably induce these afterdepolarizations, which persisted under blockade of ionotropic glutamate (kynurenic acid, 2 mM), GABAA (picrotoxin, 50 μM), GABAB (CGP 55845, 1 μM), and acetylcholine nicotinic receptors (DHβE, 2 μM). However, this effect was blocked by atropine (2 μM; nonselective muscarinic antagonist) or tetrodotoxin (0.5 μM). Finally, the muscarinic-dependent afterdepolarizations were sensitive to Ca2+-sensitive nonspecific cationic (CAN) channel blockade. Hence, these data suggest that muscarinic receptor activation during HFS can lead to feedforward excitation through the opening of CAN channels. This study for the first time describes a cholinergic mechanism of HFS in EP neurons and provides new insight into the underlying mechanisms of DBS.

High Frequency Vibration of Worst Ear Lobule induced short period of Rapid Inhibition of any Cancer Activity including Advanced Terminal Cancers, Most Malignant Brain Tumor "Glioblastoma" as well as Cancer of Lung, Breast & Gastrointestinal Cancers particularly Pancreatic Cancer.

2020 ◽  
Vol 44 (3) ◽  
pp. 241-249
Author(s):  
Yoshiaki Omura
Keyword(s):  
Pancreatic Cancer ◽  
Vitamin D3 ◽  
High Frequency ◽  
Optimal Dose ◽  
High Frequency Stimulation ◽  
Frequency Stimulation ◽  
Short Time ◽  
The Brain ◽  
Cancer Activity ◽  
Stimulation Of

While a visiting Professor at the University of Paris, VI (formerly Sorvonne) more than 40 years ago, the Author became very good friends with Dr. Paul Nogier who periodically gave seminars and workshops in Paris. After the author diagnosed his cervical problem & offered him simple help, Dr. Nogier asked the Author to present lectures and demonstrations on the effects of ear stimulation, namely the effects of acupuncture & electrical stimulation of the ear lobules. It is only now, in 2019 that we have discovered 2–5 minute high frequency stimulation of the ear lobule inhibits cancer activity for 1– 4 hours post stimulation. Although the procedure is extremely simple. First take optimal dose of Vitamin D3, which has the most essential 10 unique beneficial factors required for every human cell activity. Next, apply high frequency stimulation to ear lobule while the worst ear lobule is held by all fingers with vibrator directly touching the surface of the worst ear lobule, preferably after patient repeatedly takes optimal dose of Vitamin D3. When the worst ear lobule is held between thumb & index fingers and applying mechanical stimulation of 250 ~ 500 mechanical vibration/second for 2 ~ 5 minutes using an electrical vibrator, there is rapid disappearance of cancer activity in both the brain and rest of the body for short time duration 1 ~ 4 hours. The effect often increases by additional pressure by holding fingers. As of May 2019, the Author found that many people from various regions of the world developed early stages of multiple cancers. For evaluation of this study, U. S. patented Bi-Digital O-Ring Test (BDORT) was used which was developed by the Author while doing his Graduate experimental physics research at Colombia University. BDORT was found to be most essential for determining the beneficial effects as well as harmful effects of any substance or treatment. Using BDORT, Author was the first to recognize severe increasing mid-backache was an early sign of pancreatic cancer of President of New York State Board of Medicine after top pain specialists failed to detect the cause after 3 years of effort, while the BDORT showed early stages of cancer whereas conventional X-Ray of the pancreas did not show any cancer image until 2 months after Author detected with BDORT. For example, the optimal dose of the banana is usually about 2.0 - 2.5 millimeters cross section of the banana. A whole banana is more than 50 ~ 100 times the optimal dose. Any substance eaten in more than 25 times of its optimal dose becomes highly toxic and creates DNA mutations which can cause multiple malignancies in the presence of strong electro-magnetic field. With standard medication given by doctor, patients often become sick and they are unable to reduce body weight, unless medication is reduced or completely stopped. When the amount of zinc is very high, DNA often becomes unstable and multiple cancers can grow rapidly in the presence of strong electromagnetic field. Large amount of Vitamin C from regular orange or orange juice inhibit the most important Vitamin D3 effects. At least 3 kinds of low Vitamin C oranges will not inhibit Vitamin D3. Since B12 particularly methyl cobalamin which is a red small tablet is known to improve brain circulation very significantly we examined its effect within 20 seconds of oral intake we found the following very significant changes. Acetylcholine in both sides of the brain often increases over 4,500 ng. Longevity gene Sirtuin 1 level increases significantly for short time of few hours. Thymosin α1 and Thymosinβ4 both increase to over 1500 ng from 20 ng or less.

Sign in / Sign up

Export Citation Format

Share Document