Modulation of Burst Frequency, Duration, and Amplitude in the Zero-Ca2+ Model of Epileptiform Activity

1999 ◽  
Vol 82 (5) ◽  
pp. 2262-2270 ◽  
Author(s):  
Marom Bikson ◽  
Rahul S. Ghai ◽  
Scott C. Baraban ◽  
Dominique M. Durand
Keyword(s):  
Electric Fields ◽  
Neuronal Excitability ◽  
Cell Function ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Burst Frequency ◽  
Pharmacological Agents ◽  
Low Concentration ◽  
Burst Amplitude

Incubation of hippocampal slices in zero-Ca2+ medium blocks synaptic transmission and results in spontaneous burst discharges. This seizure-like activity is characterized by negative shifts (bursts) in the extracellular field potential and a K+ wave that propagates across the hippocampus. To isolate factors related to seizure initiation, propagation, and termination, a number of pharmacological agents were tested. K+ influx and efflux mechanisms where blocked with cesium, barium, tetraethylammonium (TEA), and 4-aminopyridine (4-AP). The effect of the gap junction blockers, heptanol and octanol, on zero-Ca2+ bursting was evaluated. Neuronal excitability was modulated with tetrodotoxin (TTX), charge screening, and applied electric fields. Glial cell function was examined with a metabolism antagonist (fluroacetate). Neuronal hyperpolarization by cation screening or applied fields decreased burst frequency but did not affect burst amplitude or duration. Heptanol attenuated burst amplitude and duration at low concentration (0.2 mM), and blocked bursting at higher concentration (0.5 mM). CsCl2 (1 mM) had no effect, whereas high concentrations (1 mM) of BaCl2 blocked bursting. TEA (25 mM) and low concentration of BaCl2 (300 μM) resulted in a two- to sixfold increase in burst duration. Fluroacetate also blocked burst activity but only during prolonged application (>3 h). Our results demonstrate that burst frequency, amplitude, and duration can be independently modulated and suggest that neuronal excitability plays a central role in burst initiation, whereas potassium dynamics establish burst amplitude and duration.

scholarly journals Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors

2020 ◽  
Author(s):  
Olha Zapukhliak ◽  
Olga Netsyk ◽  
Artur Romanov ◽  
Oleksandr Maximyuk ◽  
Murat Oz ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Muscarinic Acetylcholine Receptors ◽  
Therapeutic Effects ◽  
Hippocampal Network ◽  
Gaba Transmission

AbstractCholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we study the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, recurrent field discharges synchronous between CA3 and CA1 were recorded. Field discharges were blocked by addition of calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous field discharges, while antagonists of α7 and α4β2 nAChRs – MLA and DhβE had no effect. Our results suggest that activation of nicotinic acetylcholine receptors is able to sustain CA3-CA1 synchronous epileptiform activity independently from AMPA NMDA and GABA transmission. In addition, mecamylamine but not α7 and α4β2 nAChRs antagonists reduce bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.

Nonsynaptic epileptogenesis in the mammalian hippocampus in vitro. I. Development of seizurelike activity in low extracellular calcium

1986 ◽  
Vol 56 (2) ◽  
pp. 409-423 ◽  
Author(s):  
A. Konnerth ◽  
U. Heinemann ◽  
Y. Yaari
Keyword(s):  
Epileptiform Activity ◽  
Large Population ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Discharge Zone ◽  
Critical Threshold ◽  
Mean Velocity ◽  
Stratum Pyramidale ◽  
Ca1 Area

Epileptiform activity induced in rat hippocampal slices by lowering extracellular Ca2+ concentration ([Ca2+]o) was studied with extracellular and intracellular recordings. Perfusing the slices with low Ca2+ (less than or equal to 0.2 mM) or EGTA-containing solutions blocked the synaptic responses of hippocampal pyramidal cells (HPCs). Despite the block, spontaneous paroxysms, termed seizurelike events (SLEs), appeared in the CA1 area and then recurred regularly at a stable frequency. Transient hypoxia accelerated their development and increased their frequency. When [Ca2+]o was raised in a stepwise manner, the SLEs disappeared at 0.3 mM. With extracellular recording from the CA1 stratum pyramidale, a SLE was characterized by a large negative shift in the field potential, which lasted for several seconds. During this period a large population of CA1 neurons discharged intensely and often in synchrony, as concluded from the frequent appearance of population spikes. Synchronization, however, was not a necessary precursor for the development of paroxysmal activity, but seemed to be the end result of massive neuronal excitation. The cellular counterpart of a SLE, as revealed by intracellular recording from HPCs in the discharge zone of the paroxysms, was a long-lasting depolarization shift (LDS) of up to 20 mV. This was accompanied by accelerated firing of the neuron. A prolonged after-hyperpolarization succeeded each LDS and arrested cell firing. Brief (approximately 50 ms) bursts were commonly observed before LDS onset. Single electrical stimuli applied focally to the stratum pyramidale or alveus evoked paroxysms identical to the spontaneous SLEs, provided they surpassed a critical threshold intensity. Subthreshold stimuli elicited only small local responses, whereas stimuli of varied suprathreshold intensities evoked the same maximal SLEs. Thus the buildup of a SLE is an all or nothing or a regenerative process, which mobilizes the majority, if not all, of the local neuronal population. Each SLE was followed by absolute and relative refractory periods during which focal stimulation was, respectively, ineffective and less effective in evoking a maximal SLE. In most slices the spontaneous SLEs commenced at a "focus" located in the CA1a subarea (near the subiculum). SLEs evoked by focal stimulation arose near the stimulating electrode. From their site of origin the paroxysmal discharges spread transversely through the entire CA1 area at a mean velocity of 1.74 mm/s. Consequently, the discharge zone of a SLE could encompass for several seconds the entire CA1 area.(ABSTRACT TRUNCATED AT 400 WORDS)

Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

2002 ◽  
Vol 87 (1) ◽  
pp. 62-71 ◽  
Author(s):  
Marom Bikson ◽  
Scott C. Baraban ◽  
Dominique M. Durand
Keyword(s):  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Seizure Threshold ◽  
Ion Selective Electrodes ◽  
Receptor Antagonists ◽  
Sodium Conductance ◽  
Ca1 Region ◽  
Persistent Sodium Conductance

Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca2+ concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca2+ levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca2+ reduction in normal Ca2+ levels. Increasing neuronal excitability, by removing extracellular Mg2+ and increasing extracellular K+ (6–15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [d-(−)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of KCaantagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba2+) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg2+ and increasing extracellular K+) in the presence of Cd2+, a nonselective Ca2+channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca2+ facilitates bursting by increasing neuronal excitability and inhibiting Ca2+ influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca2+ levels.

scholarly journals Hyperoxic stimulation of synchronous orthodromic activity and induction of neural plasticity does not require changes in excitatory synaptic transmission

2010 ◽  
Vol 109 (3) ◽  
pp. 820-829 ◽  
Author(s):  
Alfredo J. Garcia ◽  
Robert W. Putnam ◽  
Jay B. Dean
Keyword(s):  
Synaptic Transmission ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Excitatory Synaptic Transmission ◽  
Population Spike ◽  
Excitatory Postsynaptic Potential ◽  
Synaptic Activation ◽  
Ca1 Neurons ◽  
Stimulation Of

The first study, described in the companion article, reports that acute exposure of rat hippocampal slices to either hyperbaric oxygen (HBO: 2.84 and 4.54 atmospheres absolute, ATA) or normobaric reoxygenation (NBOreox; i.e., normobaric hyperoxia: 0.6 or 0.0 → 0.95 ATA) stimulates synchronous orthodromic activity in CA1 neurons, which includes activation of O2-induced potentiation (OxIP) and, in some cases, hyperexcitability (secondary population spikes, sPS). In this second study we tested the hypothesis that HBO and NBOreox increase orthodromic activity of CA1 neurons (oPS, orthodromic population spike) and OxIP via a combination of both increased excitatory synaptic transmission (field excitatory postsynaptic potential, fEPSP) and intrinsic excitability (antidromic population spike, aPS). HBO and NBOreox increased the oPS but rarely increased or potentiated the fEPSP. HBO exposure produced epileptiform antidromic activity, which was abolished during inhibition of fast GABAergic and glutamatergic synaptic transmission. Decreasing O2 from 0.95 ATA (control) to 0.6 ATA (intermediate O2) or 0.0 ATA (hypoxia) reversibly abolished the fEPSP, and reoxygenation rarely induced potentiation of the fEPSP or aPS. Intracellular recordings and antidromic field potential recordings, however, revealed that synaptic transmission and neuronal excitability were preserved, albeit at lower levels, in 0.60 ATA O2. Together, these data indicate that 1) the changes in excitatory postsynaptic activity are not required for stimulation of the oPS during and HBO/NBOreox or for activation of OxIP, suggesting the latter is a form of intrinsic plasticity; 2) HBO disinhibits spontaneous synaptic transmission to induce epileptiform activity; and 3) although synchronous synaptic activation of the CA1 neuronal population requires hyperoxia (i.e., 0.95 ATA O2), synaptic activation of individual CA1 neurons does not.

scholarly journals BAD and KATP channels regulate neuron excitability and epileptiform activity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Juan Ramón Martínez-François ◽  
María Carmen Fernández-Agüera ◽  
Nidhi Nathwani ◽  
Carolina Lahmann ◽  
Veronica L Burnham ◽  
...  
Keyword(s):  
Katp Channel ◽  
Neuronal Excitability ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Epileptic Seizures ◽  
Katp Channels ◽  
Brain Cell ◽  
Channel Activity

Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity.

Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices

1987 ◽  
Vol 57 (3) ◽  
pp. 869-888 ◽  
Author(s):  
I. Mody ◽  
J. D. Lambert ◽  
U. Heinemann
Keyword(s):  
Spontaneous Activity ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Transient Field ◽  
Free Medium ◽  
Normal Medium ◽  
Postsynaptic Potentials ◽  
Population Spikes ◽  
Ca1 Region

The effect of low extracellular Mg2+ concentration ([Mg2+]o) on neuronal activity was studied in rat hippocampal slices. After 20–40 min of perfusion with Mg2+-free medium, when [Mg2+]o declined to approximately 0.1–0.4 mM, spontaneous field potentials developed in the CA1 and CA3 regions, but not in the dentate gyrus. In the CA3 pyramidal cell layer, these potentials consisted of repetitive (0.3–0.5 Hz), 40- to 120-ms-long positive deflections (2–5 mV) with superimposed population spikes. In the stratum (str.) pyramidale of the CA1 region, positive-negative deflections (less than 3 mV) lasting for 30–80 ms were observed, which occurred with a frequency of 0.3-0.5 Hz. In some cases, longer lasting and rapidly recurring events were also observed. In CA3 pyramidal cells, the intracellular correlates of the field potential transients were 20- to 30-mV paroxysmal depolarization shifts (PDS) with superimposed bursts of action potentials, followed by large (greater than 10 mV), 500- to 1,200-ms-long afterhyperpolarizations (AHP). In contrast, pyramidal neurons of the CA1 area did not show PDSs; instead, sequences of excitatory postsynaptic potentials (EPSPs)/inhibitory postsynaptic potentials (IPSPs) accompanied the transient field potential changes. Occasionally, spontaneous EPSPs/IPSPs, occurring with high frequencies, could also be observed in CA1 without any field potential transients. In both hippocampal regions, the epileptiform activity evolved without significant alterations in the resting membrane potential (RMP) and input resistance (RN) of the neurons, although a 2- to 5-mV reduction in action potential threshold was noted. The spontaneous activity in Mg2+-free medium was readily suppressed by raising the extracellular Ca2+ concentration ([Ca2+]o) from 1.6 to 3.6 mM. The perfusion of 10-30 microns DL-2-amino-5-phosphonovaleric acid (2-APV), an antagonist for the glutamate receptors of the N-methyl-D-aspartate (NMDA) type, also attenuated or reversibly blocked the spontaneous activity. Surgical isolation of area CA1 from CA3 ceased the occurrence of the transients in CA1 but not in CA3. The synaptic input/output curves were shifted to the left in the absence of [Mg2+]o. Threshold intensity for eliciting population spikes was 50-75% of that in normal medium. Paired-pulse facilitation was still present near threshold, but was reduced at higher stimulus intensities. Decreases in [Ca2+]o, produced by repetitive stimulation (20-Hz/5-10 s) of the Schaffer collateral/commissural pathway and monitored with ion-selective microelectrodes in the CA1 region, were enhanced in Mg2+-free medium.(ABSTRACT TRUNCATED AT 400 WORDS)

Synaptic Regulation of the Slow Ca2+-Activated K+ Current in Hippocampal CA1 Pyramidal Neurons: Implication in Epileptogenesis

2001 ◽  
Vol 86 (6) ◽  
pp. 2878-2886 ◽  
Author(s):  
Eduardo D. Martín ◽  
Alfonso Araque ◽  
Washington Buño
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Epileptiform Activity ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Cooperative Action ◽  
Epileptiform Discharges ◽  
Group I

The slow Ca2+-activated K+ current (sIAHP) plays a critical role in regulating neuronal excitability, but its modulation during abnormal bursting activity, as in epilepsy, is unknown. Because synaptic transmission is enhanced during epilepsy, we investigated the synaptically mediated regulation of the sIAHP and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP+Mg2+-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca2+ techniques to analyze the sIAHP modifications that parallel epileptiform activity. Epileptiform activity was characterized by slow, repetitive, spontaneous depolarizations and action potential bursts and was associated with increased frequency and amplitude of spontaneous excitatory postsynaptic currents and a reduced sIAHP. The metabotropic glutamate receptor (mGluR) antagonist (S)-α-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sIAHP inhibition and epileptiform discharges. The mGluR-dependent regulation of the sIAHP was not caused by modulated intracellular Ca2+ signaling. Histamine, isoproterenol, and (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid reduced the sIAHP but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP+Mg-free–induced enhancement of synaptic activity reduced the sIAHP via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sIAHP contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.

scholarly journals Epileptiform activity and spreading depolarization in the blood–brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity

2016 ◽  
Vol 37 (5) ◽  
pp. 1803-1819 ◽  
Author(s):  
Kristina Lippmann ◽  
Lyn Kamintsky ◽  
Soo Young Kim ◽  
Svetlana Lublinsky ◽  
Ofer Prager ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Blood Brain Barrier ◽  
Vasogenic Edema ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Output Analysis ◽  
Blood Brain

Peri-infarct opening of the blood–brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood–brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood–brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input–output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.

Calcium-Activated Afterhyperpolarizations Regulate Synchronization and Timing of Epileptiform Bursts in Hippocampal CA3 Pyramidal Neurons

2006 ◽  
Vol 96 (6) ◽  
pp. 3028-3041 ◽  
Author(s):  
David Fernández de Sevilla ◽  
Julieta Garduño ◽  
Emilio Galván ◽  
Washington Buño
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Epileptiform Activity ◽  
Network Activity ◽  
Cellular Mechanisms ◽  
Burst Frequency ◽  
Potassium Conductances ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Neurons

Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca2+-activated K+-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg2+-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO4 reduced burst frequency. Block of GABAA–B inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.

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