scholarly journals Synergistic Roles of GABAA Receptors and SK Channels in Regulating Thalamocortical Oscillations

2009 ◽  
Vol 102 (1) ◽  
pp. 203-213 ◽  
Author(s):  
Max Kleiman-Weiner ◽  
Mark P. Beenhakker ◽  
William A. Segal ◽  
John R. Huguenard
Keyword(s):  
Brain Slices ◽  
Absence Epilepsy ◽  
Cellular Level ◽  
Reticular Nucleus ◽  
Sk Channels ◽  
Sk Channel ◽  
Spike Wave Discharges ◽  
Thalamocortical Oscillations ◽  
The Brain

Rhythmic oscillations throughout the cortex are observed during physiological and pathological states of the brain. The thalamus generates sleep spindle oscillations and spike-wave discharges characteristic of absence epilepsy. Much has been learned regarding the mechanisms underlying these oscillations from in vitro brain slice preparations. One widely used model to understand the epileptiform oscillations underlying absence epilepsy involves application of bicuculline methiodide (BMI) to brain slices containing the thalamus. BMI is a well-known GABAA receptor blocker that has previously been discovered to also block small-conductance, calcium-activated potassium (SK) channels. Here we report that the robust epileptiform oscillations observed during BMI application rely synergistically on both GABAA receptor and SK channel antagonism. Neither application of picrotoxin, a selective GABAA receptor antagonist, nor application of apamin, a selective SK channel antagonist, alone yielded the highly synchronized, long-lasting oscillations comparable to those observed during BMI application. However, partial blockade of SK channels by subnanomolar concentrations of apamin combined with picrotoxin sufficiently replicated BMI oscillations. We found that, at the cellular level, apamin enhanced the intrinsic excitability of reticular nucleus (RT) neurons but had no effect on relay neurons. This work suggests that regulation of RT excitability by SK channels can influence the excitability of thalamocortical networks and may illuminate possible pharmacological treatments for absence epilepsy. Finally, our results suggest that changes in the intrinsic properties of individual neurons and changes at the circuit level can robustly modulate these oscillations.

TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Breanna Mann ◽  
Noah Bell ◽  
Denise Dunn ◽  
Scott Floyd ◽  
Shawn Hingtgen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Brain Cancer ◽  
Brain Slice ◽  
Brain Slices ◽  
In Vitro Assays ◽  
Preclinical Model ◽  
Short Period ◽  
The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

scholarly journals Differential effects of propofol and ketamine on critical brain dynamics

2020 ◽  
Vol 16 (12) ◽  
pp. e1008418
Author(s):  
Thomas F. Varley ◽  
Olaf Sporns ◽  
Aina Puce ◽  
John Beggs
Keyword(s):  
Cellular Level ◽  
Brain Dynamics ◽  
Neuronal Cultures ◽  
Altered States ◽  
Differential Effects ◽  
States Of Consciousness ◽  
Anaesthetized Rats ◽  
And Control ◽  
The Brain

Whether the brain operates at a critical “tipping” point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as “dissociative anaesthesia”). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.

scholarly journals The metabolism of polyphosphoinositides in hen brain and sciatic nerve

1969 ◽  
Vol 111 (2) ◽  
pp. 157-165 ◽  
Author(s):  
A. Sheltawy ◽  
R. M. C. Dawson
Keyword(s):  
Sciatic Nerve ◽  
Previous Investigation ◽  
Relative Rate ◽  
Specific Radioactivity ◽  
Brain Slices ◽  
Soluble Phosphorus ◽  
Ethanolamine Plasmalogen ◽  
32P Incorporation ◽  
The Brain

1. The distribution of individual phospholipids was determined in hen brain and compared with that in sciatic nerve obtained in a previous investigation. Sciatic nerve is more enriched in the myelinic phospholipids ethanolamine plasmalogen, phosphatidylserine and sphingomyelin, but it contains relatively less triphosphoinositide, and much less diphosphoinositide, than the brain. 2. The course of incorporation of intraperitoneally injected 32P into the acid-soluble phosphorus, phosphoinositides and total phospholipids of hen brain and sciatic nerve was followed. Although the maximum specific radioactivity in sciatic nerve of acid-soluble phosphorus is 4·5 times, and that of triphosphoinositide six times, that in the brain, the relative rate of triphosphoinositide phosphorus synthesis per gram of brain is three times that in sciatic nerve. 3. Administration of the demyelinating agent tri-o-cresyl phosphate to hens has no significant effect on the amounts or the rate of 32P incorporation into the total phospholipids of the sciatic nerve. However, the rate of incorporation of 32P into triphosphoinositide, although not its concentration, is raised from the first day after administration of the drug and remains thus 13 and 23 days later. 4. The incorporation of 32P into polyphosphoinositides of hen brain slices in vitro was studied. The recovery of triphosphoinositide from the slices is markedly increased in the presence of EDTA, although the rate of incorporation of 32P is unaffected. The incorporation of 32P is dependent on the presence of Mg2+ and Ca2+ in the medium, and is decreased when Na+ is replaced with K+ or cholinium ions.

Effect of Withdrawal from Chronic Ethanol Ingestion on the cAMP Response of Cerebral Cortical Slices Using the Agonists Histamine, Serotonin, and Other Neurotransmitters

1975 ◽  
Vol 53 (2) ◽  
pp. 248-255 ◽  
Author(s):  
Samuel W. French ◽  
Douglas S. Palmer ◽  
Mary E. Narod
Keyword(s):  
Brain Slices ◽  
Ethanol Withdrawal ◽  
Aminobutyric Acid ◽  
Ethanol Ingestion ◽  
Evoked Responses ◽  
Alternative Hypotheses ◽  
Adrenergic Antagonists ◽  
The Brain ◽  
Cortical Slices

The effect of ethanol withdrawal on the cAMP response of cerebral cortical brain slices was studied. The cAMP response was evoked in vitro by various neurotransmitters including norepinephrine (NE), histamine, serotonin, dopamine, acetylcholine, and γ-aminobutyric acid (GABA). The cAMP response to NE and histamine was enhanced by ethanol withdrawal. Serotonin evoked a cAMP response in the brain slices from ethanol-withdrawal rats but not in pair-fed controls. The histamine and serotonin evoked responses were blocked by chlortripolon and methysergide, respectively. The responses to histamine and serotonin were also blocked by a- and β-adrenergic antagonists, possibly because of the nonspecific membrane stabilizing effect of these antagonists. GABA inhibited the NE stimulated cAMP response possibly through the hyperpolarizing action of GABA. The results support the hypothesis that ethanol withdrawal induces a nonspecific postjunctional supersensitivity. It is postulated that the supersensitivity involves a partial depolarization of the receptor membrane. Alternative hypotheses are reviewed.

scholarly journals Cestode larvae excite host neuronal circuits via glutamatergic signaling

2019 ◽  
Author(s):  
Hayley Tomes ◽  
Anja de Lange ◽  
Ulrich Fabien Prodjinotho ◽  
Siddhartha Mahanty ◽  
Katherine Smith ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Imaging Techniques ◽  
Taenia Solium ◽  
Brain Slices ◽  
Receptor Activation ◽  
Excitatory Effect ◽  
Excitatory Neurotransmitter ◽  
Acquired Epilepsy ◽  
The Brain

AbstractNeurocysticercosis (NCC) is caused by the presence of Taenia solium larvae in the brain and is the leading cause of adult-acquired epilepsy worldwide. However, little is known about how seizures emerge in NCC. To address this knowledge gap we used whole-cell patch-clamp electrophysiology and calcium imaging in rodent hippocampal organotypic slice cultures to identify direct effects of cestode larval products on neuronal activity. We found both whole cyst homogenate and excretory/secretory (E/S) products of Taenia larvae have an acute excitatory effect on neurons, which trigger seizure-like events in vitro. Underlying this effect was Taenia-induced neuronal depolarization, which was mediated by glutamate receptor activation but not by nicotinic acetylcholine receptors, acid-sensing ion channels nor Substance P. Glutamate assays revealed the homogenate of both Taenia crassiceps and Taenia solium larvae contained high concentrations of glutamate and that larvae of both species consistently produce and release this excitatory neurotransmitter into their immediate environment. These findings contribute towards the understanding of seizure generation in NCC.Author summaryBrain infection by larvae of the tapeworm Taenia solium (neurocysticercosis or NCC) is the leading cause of acquired epilepsy in adulthood. Little is understood about the mechanisms by which larvae cause seizures. To address this, we used electrophysiological and imaging techniques in rodent brain slices to investigate how tapeworm larvae directly impact neuronal function. We discovered that both the homogenate and secretory products of tapeworm larvae excite neurons and can trigger seizure-like events in brain slices. This effect was caused by the activation of glutamate receptors and not by activating other types of receptors in the brain. Finally, we observed that tapeworm larvae both contain and release the neurotransmitter glutamate into their immediate environment. These findings are relevant for understanding how tapeworm larvae cause seizures in NCC.

Biochemistry

1936 ◽  
Vol 82 (339) ◽  
pp. 431-433
Author(s):  
J. H. Quastel
Keyword(s):  
Nervous System ◽  
Brain Tissue ◽  
Brain Slice ◽  
Brain Slices ◽  
Ringer Solution ◽  
Living Animal ◽  
Dominant Form ◽  
Straight Line ◽  
The Brain

I want to speak of the work we have been doing in Cardiff on the metabolism of the nervous system. The work was carried out there because of the importance of the narcosis treatment. It seemed to us there a pity that a treatment such as that should be given up because of the considerable toxicity possible in relation to it. The research was undertaken to see if we could diminish the toxicity, at the same time seeking an idea as to how narcotics work. I ask that you will realize that the main substance burned by the brain is glucose. The dominant form of metabolism in the nervous system is connected with the breakdown of glucose and lactic acid, and this can be proved by experiment in the living animal and with brain-tissue in vitro. In doing experiments we are not able to carry out work with human brain, because we cannot get human tissue fresh enough, so we have to carry out experiments with animals. They are carried out in this way. We cut slices of the cortex of the brain as soon as the animal is dead, that is to say, within ten minutes of death the brain is out and slices have been cut. They are placed in a physiological medium in the presence of glucose, and we follow the metabolism of that tissue, which allows us to estimate the amount of oxygen being taken up by the brain. If luminal, chloretone, hyoscine or somnifaine be placed with the brain-tissue, then the respiration, instead of being at the usual level, starts lower down, and maintains a straight line. We wanted to see whether this action is reversible or irreversible. If the latter, then on removing the brain-slices from the narcotic it should no longer behave like a normal piece of tissue. Actually, when the brain-slice is removed and placed in Ringer solution, with no narcotic, the respiration goes up and becomes equal to that shown by the slice which had no narcotic. That is to say, the process is reversible.

scholarly journals Spindle-Like Thalamocortical Synchronization in a Rat Brain Slice Preparation

2000 ◽  
Vol 84 (2) ◽  
pp. 1093-1097 ◽  
Author(s):  
Virginia Tancredi ◽  
Giuseppe Biagini ◽  
Margherita D'Antuono ◽  
Jacques Louvel ◽  
René Pumain ◽  
...  
Keyword(s):  
Rat Brain ◽  
Kynurenic Acid ◽  
Brain Slice ◽  
Excitatory Amino Acid ◽  
Brain Slices ◽  
Reticular Nucleus ◽  
Antidromic Responses ◽  
Rat Brain Slice

We obtained rat brain slices (550–650 μm) that contained part of the frontoparietal cortex along with a portion of the thalamic ventrobasal complex (VB) and of the reticular nucleus (RTN). Maintained reciprocal thalamocortical connectivity was demonstrated by VB stimulation, which elicited orthodromic and antidromic responses in the cortex, along with re-entry of thalamocortical firing originating in VB neurons excited by cortical output activity. In addition, orthodromic responses were recorded in VB and RTN following stimuli delivered in the cortex. Spontaneous and stimulus-induced coherent rhythmic oscillations (duration = 0.4–3.5 s; frequency = 9–16 Hz) occurred in cortex, VB, and RTN during application of medium containing low concentrations of the K+ channel blocker 4-aminopyridine (0.5–1 μM). This activity, which resembled electroencephalograph (EEG) spindles recorded in vivo, disappeared in both cortex and thalamus during application of the excitatory amino acid receptor antagonist kynurenic acid in VB ( n = 6). By contrast, cortical application of kynurenic acid ( n = 4) abolished spindle-like oscillations at this site, but not those recorded in VB, where their frequency was higher than under control conditions. Our findings demonstrate the preservation of reciprocally interconnected cortical and thalamic neuron networks that generate thalamocortical spindle-like oscillations in an in vitro rat brain slice. As shown in intact animals, these oscillations originate in the thalamus where they are presumably caused by interactions between RTN and VB neurons. We propose that this preparation may help to analyze thalamocortical synchronization and to understand the physiopathogenesis of absence attacks.

Properties and expression of Ca2+-activated K+ channels in H9c2 cells derived from rat ventricle

1999 ◽  
Vol 276 (5) ◽  
pp. H1559-H1566 ◽  
Author(s):  
Wei Wang ◽  
Makino Watanabe ◽  
Takeshi Nakamura ◽  
Yoshihisa Kudo ◽  
Rikuo Ochi
Keyword(s):  
Time Course ◽  
External Solution ◽  
Pcr Analysis ◽  
Sk Channels ◽  
Sk Channel ◽  
Current Voltage ◽  
Rat Ventricle ◽  
Current Voltage Relation ◽  
Small Conductance

H9c2 is a clonal myogenic cell line derived from embryonic rat ventricle that can serve as a surrogate for cardiac or skeletal muscle in vitro. Using whole cell clamp with H9c2 myotubes, we observed that depolarizing pulses activated slow outward K+ currents and then slow tail currents. The K+ currents were abolished in a Ca2+-free external solution, indicating that they were Ca2+-activated K+ currents. They were blocked by apamin, a small-conductance Ca2+-activated K+ (SK) channel antagonist (IC50 = 6.2 nM), and by d-tubocurarine (IC50 = 49.4 μM). Activation of SK channels exhibited a bell-shaped voltage dependence that paralleled the current-voltage relation for L-type Ca2+ currents ( I Ca,L). I Ca,L exhibited a slow time course similar to skeletal I Ca,L, were unaffected by apamin, and were only slightly depressed by d-tubocurarine. RT-PCR analysis of the mRNAs revealed that rSK3, but not rSK1 or rSK2, was expressed in H9c2 myotubes but not in myoblasts. These results suggest that rSK3 channels are expressed in H9c2 myotubes and are primarily activated by I Ca,L directly or indirectly via Ca2+-induced Ca2+ release from sarcoplasmic reticulum.

scholarly journals Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ernesto Flores-Martínez ◽  
Fernando Peña-Ortega
Keyword(s):  
Prefrontal Cortex ◽  
Brain Slices ◽  
Amyloid Β ◽  
Network Activity ◽  
Amyloid Β Peptide ◽  
Cell Level ◽  
Long Range Interactions ◽  
Induced Changes ◽  
The Brain

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain’s amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

A Modeling Study Suggests Complementary Roles for GABAA and NMDA Receptors and the SK Channel in Regulating the Firing Pattern in Midbrain Dopamine Neurons

2004 ◽  
Vol 91 (1) ◽  
pp. 346-357 ◽  
Author(s):  
Alexander O. Komendantov ◽  
Olena G. Komendantova ◽  
Steven W. Johnson ◽  
Carmen C. Canavier
Keyword(s):  
Experimental Data ◽  
Firing Pattern ◽  
Receptor Activation ◽  
Burst Firing ◽  
Dopamine Neurons ◽  
Sk Channels ◽  
Sk Channel ◽  
The Difference

Midbrain dopaminergic (DA) neurons in vivo exhibit two major firing patterns: single-spike firing and burst firing. The firing pattern expressed is dependent on both the intrinsic properties of the neurons and their excitatory and inhibitory synaptic inputs. Experimental data suggest that the activation of N-methyl-d-aspartate (NMDA) and GABAA receptors is a crucial contributor to the initiation and suppression of burst firing, respectively, and that blocking Ca2+-activated potassium SK channels can facilitate burst firing. A multi-compartmental model of a DA neuron with a branching structure was developed and calibrated based on in vitro experimental data to explore the effects of different levels of activation of NMDA and GABAA receptors as well as the modulation of the SK current on the firing activity. The simulated tonic activation of GABAA receptors was calibrated by taking into account the difference in the electrotonic properties in vivo versus in vitro. Although NMDA-evoked currents are required for burst generation in the model, currents evoked by GABAA-receptor activation can also regulate the firing pattern. For example, the model predicts that increasing the level of NMDA receptor activation can produce excessive depolarization that prevents burst firing, but a concurrent increase in the activation of GABAA receptors can restore burst firing. Another prediction of the model is that blocking the SK channel current in vivo will facilitate bursting, but not as robustly as blocking the GABAA receptors.

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