Spread of synchronous firing in longitudinal slices from the CA3 region of the hippocampus

1988 ◽  
Vol 60 (4) ◽  
pp. 1481-1496 ◽  
Author(s):  
R. Miles ◽  
R. D. Traub ◽  
R. K. Wong
Keyword(s):  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Neuronal Firing ◽  
Burst Firing ◽  
Stratum Radiatum ◽  
Synaptic Inhibition ◽  
Firing Threshold ◽  
Single Action ◽  
Synchronous Firing ◽  
Ca3 Region

1. Mechanisms underlying the propagation of synchronous epileptiform activity in disinhibited hippocampal slices were examined in experimental and computer simulation studies. 2. Experiments were performed with longitudinal slices of the CA3 region. Synchronous firing was initiated by stimulating stratum radiatum fibers in the presence of picrotoxin. It propagated smoothly and without decrement at velocities close to 0.15 m/s over distances up to 10 mm. 3. In elevated extracellular calcium, neuronal firing threshold was increased and synchronous burst firing did not spread. Monophasic excitatory postsynaptic potentials (EPSPs) were recorded in cells at limited distances from a stimulus in the presence of 10 mM Ca and picrotoxin. Axonal conduction velocity, estimated from EPSP latencies, was several times faster than the spread of synchronous firing. 4. EPSPs recorded in 5-7 mM Ca and picrotoxin could consist of two components. The properties of the first component were similar to those of synaptic events recorded in 10 mM Ca. The second component was of longer latency and unlike the first component was suppressed in responses to paired stimuli at interval 50-300 ms. Recordings from cells at different distances from a stimulus suggested that the second component spread further and more slowly than the first component. 5. In computer simulations the CA3 region was represented by a spatially distributed network of 9,000 excitatory neurons and 900 inhibitory cells. Individual cells and synapses had properties based on experimental data. The effects of varying synaptic strength and connectivity on the spread of activity in the model was examined. 6. When synaptic inhibition was functional in simulations, firing was restricted to a single action potential in model cells close to the stimulus, as in experiments. Synchronous burst firing spread throughout the neuronal array when fast synaptic inhibition was absent. The velocity of propagation was slower than conduction in simulated axons when synaptic contacts made by excitatory cells were spatially limited. Propagation velocity increased with increases in the spatial extent of excitatory connectivity. 7. Increasing the threshold of neurons in a region of the model network reduced the speed at which synchronous firing spread. In experiments focal application of gamma-aminobutyric acid (GABA) elevated neuronal firing threshold and slowed the propagation of synchrony in a local region. 8. As the strength of synaptic inhibition was gradually reduced, neuronal activity spread further and faster through the simulated neuronal network.(ABSTRACT TRUNCATED AT 400 WORDS)

Osmotic effects on the CA1 neuronal population in hippocampal slices with special reference to glucose

1991 ◽  
Vol 65 (5) ◽  
pp. 1055-1066 ◽  
Author(s):  
B. A. Ballyk ◽  
S. J. Quackenbush ◽  
R. D. Andrew
Keyword(s):  
Action Potential ◽  
Single Cell ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Stratum Radiatum ◽  
Resting Potential ◽  
Excitatory Postsynaptic Potential ◽  
Stratum Pyramidale ◽  
Postsynaptic Potential ◽  
Axonal Excitability

1. Lowered osmolality promotes epileptiform activity both clinically and in the hippocampal slice preparation, but it is unclear how neurons are excited. We studied the effects of altered osmolality on the electrophysiological properties of CA1 pyramidal cells in hippocampal slices by the use of field and intracellular recordings. The excitability of these neurons under various osmotic conditions was gauged by population spike (PS) amplitude, single cell properties, and evoked synaptic input. 2. The orthodromic PS recorded in stratum pyramidale and the field excitatory postsynaptic potential (EPSP) in stratum radiatum were inversely proportional in amplitude to the artificial cerebrospinal fluid (ACSF) osmolality over a range of +/- 80 milliosmoles/kgH2O (mosM). The effect was osmotic because changes occurred within the time frame expected for cellular expansion or shrinkage and because permeable substances such as dimethyl sulfoxide or glycerol were without effect. Dilutional changes in ACSF constituents were experimentally ruled out as promoting excitability. 3. To test whether the field data resulted from a change in single-cell excitability, CA1 cells were intracellularly recorded during exposure to +/- 40 mosM ACSF over 15 min. There was no consistent effect upon CA1 resting potential, cell input resistance, or action potential threshold. 4. Osmotic alteration of orthodromic and antidromic field potentials might involve a change in axonal excitability. However, the evoked afferent volley recorded in CA1 stratum pyramidale or radiatum, which represents the compound action potential (CAP) generated in presynaptic axons, remained osmotically unresponsive with regard to amplitude, duration, or latency. This was also characteristic of CAPs evoked in isolated sciatic and vagus nerve preparations exposed to +/- 80 mosM. Therefore axonal excitability and associated extracellular current flow generated periaxonally are not significantly affected by osmotic shifts. 5. The osmotic effect on field potential amplitudes appeared to be independent of synaptic transmission because the inverse relationship with osmolality held for the antidromically evoked PS. Moreover, as recorded with respect to ground, the intracellular EPSP-inhibitory postsynaptic potential (IPSP) sequence (evoked from CA3 stratum radiatum) was not altered by osmolality. 6. The PS could occasionally be recorded intracellularly as a brief negativity interrupting the evoked EPSP. In hyposmotic ACSF, the amplitude increased and action potentials arose from the trough of the negativity as expected for a field effect. This is presumably the result of enhanced intracellular channeling of current caused by the increased extracellular resistance that accompanies cellular swelling.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals KCNQ/Kv7 Channel Regulation of Hippocampal Gamma-Frequency Firing in the Absence of Synaptic Transmission

2006 ◽  
Vol 95 (5) ◽  
pp. 3105-3112 ◽  
Author(s):  
S. Piccinin ◽  
A. D. Randall ◽  
J. T. Brown
Keyword(s):  
Synaptic Transmission ◽  
High Frequency ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Neuronal Firing ◽  
Population Spike ◽  
Channel Blockers ◽  
Kv7 Channels ◽  
Population Spikes ◽  
Gamma Frequency

Synchronous neuronal firing can be induced in hippocampal slices in the absence of synaptic transmission by lowering extracellular Ca2+ and raising extracellular K+. However, the ionic mechanisms underlying this nonsynaptic synchronous firing are not well understood. In this study we have investigated the role of KCNQ /Kv7 channels in regulating this form of nonsynaptic bursting activity. Incubation of rat hippocampal slices in reduced (<0.2 mM) [Ca2+]o and increased (6.3 mM) [K+]o, blocked synaptic transmission, increased neuronal firing, and led to the development of spontaneous periodic nonsynaptic epileptiform activity. This activity was recorded extracellularly as large (4.7 ± 1.9 mV) depolarizing envelopes with superimposed high-frequency synchronous population spikes. These intraburst population spikes initially occurred at a high frequency (about 120 Hz), which decayed throughout the burst stabilizing in the gamma-frequency band (30–80 Hz). Further increasing [K+]o resulted in an increase in the interburst frequency without altering the intraburst population spike frequency. Application of retigabine (10 μM), a Kv7 channel modulator, completely abolished the bursts, in an XE-991–sensitive manner. Furthermore, application of the Kv7 channel blockers, linopirdine (10 μM) or XE-991 (10 μM) alone, abolished the gamma frequency, but not the higher-frequency population spike firing observed during low Ca2+/high K+ bursts. These data suggest that Kv7 channels are likely to play a role in the regulation of synchronous population firing activity.

Spontaneous interictal-like activity originates in multiple areas of the CA2-CA3 region of hippocampal slices

1994 ◽  
Vol 71 (4) ◽  
pp. 1574-1585 ◽  
Author(s):  
L. V. Colom ◽  
P. Saggau
Keyword(s):  
Guinea Pig ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Optical Recording ◽  
Objective Lens ◽  
Gamma Aminobutyric Acid ◽  
Subsequent Increase ◽  
Epileptiform Discharges ◽  
High K ◽  
Ca3 Region

1. The sites of origin of spontaneous interictal-like epileptiform activity in hippocampal slices from guinea pig, mouse, and rat were determined. A multisite fast optical recording technique using voltage-sensitive dyes and an array of 100 photodiodes was employed. The use of a low-magnification objective lens allowed the visualization of almost the entire transverse hippocampal slice. Three in vitro models of epilepsy were employed, utilizing different manipulations of the bath perfusion medium to induce epileptiform activity: 1) raising the external potassium (K+) concentration, 2) adding the potassium channel blocker 4-aminopyridine (4-AP), and 3) adding antagonists of gamma-aminobutyric acid-A (GABAA) receptors (bicuculline and picrotoxin, BIC-PTX). 2. Spontaneous epileptiform discharges were detected in each subfield of cornu ammonis (CA) but not in the dentate gyrus (DG) of each studied species. Preliminary experiments confirmed that interictal-like epileptiform activity originated in the CA2-CA3 region. Ictal-like activity was never observed in our experiments. 3. In the guinea pig, when GABAA antagonists were employed, the site of origin of spontaneous epileptiform discharges was consistently located in the CA2-CA3a region. When high K+ or 4-AP was used, this region was the most frequent site of origin. Subsequent epileptiform discharges with similar sites of origin occasionally invaded different areas of the CA2-CA3 region, revealing a variable area of occupance of epileptiform discharges. 4. In the mouse and rat, the site of origin of spontaneous discharges was invariably located in the CA3b-CA3c region independent of the epilepsy model. 5. In both the guinea pig and rat, when the CA2-CA3a region was surgically separated from the CA3b-CA3c region, independent discharges were observed in both regions. Areas that could generate discharges only under certain epileptogenic conditions were found in these species (potential sites of origin). Two independent sites of origin with different propagation patterns and area of occupance were occasionally observed within the CA2-CA3a region. 6. In the guinea pig, such lesions demonstrated that both regions can independently generate epileptiform discharges at different frequencies. When high K+ or 4-AP was employed, epileptiform activity was observed in both regions. Although BIC-PTX only generated discharges in the CA2-CA3a region, a subsequent increase in K+ induced additional discharges in the CA3b-CA3c region, revealing a potential site of origin. 7. In rat hippocampal slices with such lesions, spontaneous epileptiform discharges were observed in both CA2-CA3a and CA3b-CA3c region when 4-AP was employed.(ABSTRACT TRUNCATED AT 400 WORDS)

Agent-selective Effects of Volatile Anesthetics on GABAAReceptor–mediated Synaptic Inhibition in Hippocampal Interneurons

2001 ◽  
Vol 94 (2) ◽  
pp. 340-347 ◽  
Author(s):  
Koichi Nishikawa ◽  
M. Bruce MacIver
Keyword(s):  
Gabaa Receptor ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Volatile Anesthetics ◽  
Stratum Radiatum ◽  
Synaptic Inhibition ◽  
Gamma Aminobutyric Acid ◽  
Ca1 Region ◽  
Whole Cell Patch Clamp ◽  
Cortical Regions

Background A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal cells in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role for the maintenance of anesthesia. The aim of this study was to compare effects produced by volatile anesthetics on inhibitory postsynaptic currents (IPSCs) of rat hippocampal interneurons. Methods Pharmacologically isolated gamma-aminobutyric acid type A (GABAA) receptor-mediated IPSCs were recorded with whole cell patch-clamp techniques in visually identified interneurons of rat hippocampal slices. Neurons located in the stratum radiatum-lacunosum moleculare of the CA1 region were studied. The effects of clinically relevant concentrations (1.0 rat minimum alveolar concentration) of halothane, enflurane, isoflurane, and sevoflurane were compared on kinetics of both stimulus-evoked and spontaneous GABAA receptor-mediated IPSCs in interneurons. Results Halothane (1.2 vol% approximately 0.35 mm), enflurane (2.2 vol% approximately 0.60 mm), isoflurane (1.4 vol% approximately 0.50 mm), and sevoflurane (2.7 vol% approximately 0.40 mm) preferentially depressed evoked IPSC amplitudes to 79.8 +/- 9.3% of control (n = 5), 38.2 +/- 8.6% (n = 6), 52.4 +/- 8.4% (n = 5), and 46.1 +/- 16.0% (n = 8), respectively. In addition, all anesthetics differentially prolonged the decay time constant of evoked IPSCs to 290.1 +/- 33.2% of control, 423.6 +/- 47.1, 277.0 +/- 32.2, and 529 +/- 48.5%, respectively. The frequencies of spontaneous IPSCs were increased by all anesthetics (twofold to threefold). Thus, the total negative charge transfer mediated by GABAA receptors between synaptically connected interneurons was enhanced by all anesthetics. Conclusions Volatile anesthetics differentially enhanced GABAA receptor-mediated synaptic inhibition in rat hippocampal interneurons, suggesting that hippocampal interneuron circuits are depressed by these anesthetics in an agent-specific manner.

Neuropeptide Y5 Receptors Reduce Synaptic Excitation in Proximal Subiculum, But Not Epileptiform Activity in Rat Hippocampal Slices

2000 ◽  
Vol 83 (2) ◽  
pp. 723-734 ◽  
Author(s):  
Melisa W. Y. Ho ◽  
Annette G. Beck-Sickinger ◽  
William F. Colmers
Keyword(s):  
In Vitro Model ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Stratum Radiatum ◽  
Synaptic Excitation ◽  
Vitro Model ◽  
Area Ca3

Neuropeptide Y (NPY) potently inhibits excitatory synaptic transmission in the hippocampus, acting predominantly via a presynaptic Y2 receptor. Recent reports that the Y5 receptor may mediate the anticonvulsant actions of NPY in vivo prompted us to test the hypothesis that Y5receptors inhibit synaptic excitation in the hippocampal slice and, furthermore, that they are effective in an in vitro model of anticonvulsant action. Two putative Y5 receptor–preferring agonists inhibited excitatory postsynaptic currents (EPSCs) evoked by stimulation of stratum radiatum in pyramidal cells. We recorded initially from area CA1 pyramidal cells, but subsequently switched to cells from the subiculum, where a much greater frequency of response was observed to Y5 agonist application. Bothd-Trp32NPY (1 μM) and [ahx8–20]Pro34NPY (3 μM), a centrally truncated, Y1/Y5 agonist we synthesized, inhibited stimulus-evoked EPSCs in subicular pyramidal cells by 44.0 ± 5.7% and 51.3 ± 3.5% (mean ± SE), in 37 and 58% of cells, respectively. By contrast, the less selective centrally truncated agonist, [ahx8–20] NPY (1 μM), was more potent (66.4 ± 4.1% inhibition) and more widely effective, suppressing the EPSC in 86% of subicular neurons. The site of action of all NPY agonists tested was most probably presynaptic, because agonist application caused no changes in postsynaptic membrane properties. The selective Y1 antagonist, BIBP3226 (1 μM), did not reduce the effect of either more selective agonist, indicating that they activated presynaptic Y5 receptors. Y5 receptor–mediated synaptic inhibition was more frequently observed in slices from younger animals, whereas the nonselective agonist appeared equally effective at all ages tested. Because of the similarity with the previously reported actions of Y2 receptors, we tested the ability of Y5receptor agonists to suppress stimulus train-induced bursting (STIB), an in vitro model of ictaform activity, in both area CA3 and the subiculum. Neither [ahx8–20]Pro34NPY nord-Trp32NPY were significantly effective in suppressing or shortening STIB-induced afterdischarge, with <20% of slices responding to these agonists in recordings from CA3 and none in subiculum. By contrast, 1 μM each of [ahx8–20]NPY, the Y2 agonist, [ahx5–24]NPY, and particularly NPY itself suppressed the afterdischarge in area CA3 and the subiculum, as reported earlier. We conclude that Y5receptors appear to regulate excitability to some degree in the subiculum of young rats, but their contribution is relatively small compared with those of Y2 receptors, declines with age, and is insufficient to block or significantly attenuate STIB-induced afterdischarges.

Burst characteristics of dentate gyrus granule cells: evidence for endogenous and nonsynaptic properties

1996 ◽  
Vol 75 (1) ◽  
pp. 124-132 ◽  
Author(s):  
E. Pan ◽  
J. L. Stringer
Keyword(s):  
Dentate Gyrus ◽  
Action Potentials ◽  
Granule Cells ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Current Injection ◽  
Single Action ◽  
Epileptiform Discharges

1. Hippocampal slices bathed in 8 mM potassium and 0-added calcium exhibited spontaneous epileptiform activity in the dentate gyrus. Extracellular recording revealed recurrent prolonged bursts of population spikes and an associated negative DC shift. These episodes were very similar to the in vivo phenomenon termed maximal dentate activation (MDA). Therefore this in vitro activity will be referred to as MDA-like activity or events. 2. During the MDA-like activity, the individual granule cells exhibited a sustained depolarization that matched the duration of the negative extracellular DC shift. At the beginning of the MDA-like activity, there was a burst of action potentials. After the burst, most granule cells either continued to fire action potentials regularly or in bursts. Some cells exhibited this initial burst of activity and then a dramatic reduction in firing rate. This reduction in rate was followed by a gradual increase in the amplitude and frequency of the epileptiform activity recorded during the remainder of the MDA-like event. 3. Before and between MDA-like events, spontaneous cellular activity consisted of single action potentials and bursts of action potentials on a depolarizing envelope. In addition, depolarizing potentials, up to 13 mV, were recorded. There were no extracellular field potentials associated with these intracellularly recorded potentials. 4. In the 8 mM potassium, 0-added calcium test solution, the membrane potential threshold for burst production was significantly lower than in normal potassium and calcium medium. 5. The effect of depolarizing and hyperpolarizing current injections on the amplitude and frequency of the epileptiform activity was tested. Current injection had no effect on the frequency of the epileptiform activity recorded during the MDA-like events. However, the frequency of the cellular bursts between MDA-like events was very sensitive to current injection. Depolarizing current increased the frequency, and hyperpolarizing current decreased the frequency of the spontaneous activity. 6. This study has shown that in 8 mM potassium and 0-added calcium the granule cells of the dentate gyrus are capable of generating spontaneous bursts that appear to be mediated by endogenous mechanisms. In addition, synchronized epileptiform discharges were recorded from the granule cells at regular intervals that appear were recorded from the granule cells at regular intervals that appear to be mediated by exogenous nonsynaptic mechanisms.

Ictal Epileptiform Activity in the CA3 Region of Hippocampal Slices Produced by Pilocarpine

1998 ◽  
Vol 79 (6) ◽  
pp. 3019-3029 ◽  
Author(s):  
Paul A. Rutecki ◽  
Yili Yang
Keyword(s):  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Reversal Potential ◽  
Extracellular Potassium ◽  
Muscarinic Agonist ◽  
Epileptiform Discharges ◽  
Artificial Cerebrospinal Fluid ◽  
Discharge Duration ◽  
Interictal Discharges ◽  
Ca3 Region

Rutecki, Paul A. and Yili Yang. Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. J. Neurophysiol. 79: 3019–3029, 1998. Pilocarpine, a muscarinic agonist, produces status epilepticus that is associated with the later development of chronic recurrent seizures. When applied to rat hippocampal slices, pilocarpine (10 μM) produced brief (<200 ms) epileptiform discharges that resembled interictal activity that occurs between seizures, as well as more prolonged synchronous neuronal activation that lasted seconds (3–20 s), and was comparable to ictal or seizures-like discharges. We assessed the factors that favored ictal patterns of activity and determined the biophysical properties of the ictal discharge. The probability of observing ictal discharges was increased when extracellular potassium ([K+]o) was increased from 5 to 7.5 mM. Raising [K+]o to 10 mM resulted in loss of ictal patterns and, in 20 of 34 slices, desynchronization of epileptiform activity. Making the artificial cerebrospinal fluid (ACSF) hyposmotic favored ictal discharges at 5 mM [K+]o, but shifted 7.5 mM [K+]o ACSF patterns to interictal discharges or desynchronized activity. Conversely, increasing osmolality suppressed ictal patterns. The pilocarpine-induced ictal discharges were blocked by atropine (1 μM, n = 5), a muscarinic antagonist, and pirenzepine (1 μM, n = 6), a selective M1 receptor antagonist. Kainate/α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor blockade stopped all epileptiform activity ( n = 8). The N-methyl-d-aspartate antagonist d,l-2-amino-5-phosphonovaleric acid (100 μM, n = 34) did not change the pattern of epileptiform activity but significantly increased the rate of interictal discharges and prolonged the duration of ictal discharges. The ictal discharge was characterized intracellularly by a depolarization that was associated with action potential generation and persisted as a membrane oscillation of 4–10 Hz. The ictal oscillations reversed in polarity at −22.7 ± 2.2 mV ( n = 11) with current-clamp recordings and −20.9 ± 3.1 mV ( n = 7) with voltage-clamp recordings. The reversal potential of the ictal discharge in the presence of the γ-aminobutyric acid-A blocker bicuculline (10 μM, n = 6) was −2.2 ± 2.6 mV and was significantly different from that measured without bicuculline. Bicuculline added to 7.5 mM [K+]o and 10 μM pilocarpine did not cause epileptiform activity to change pattern but significantly increased the rate of interictal discharges and prolonged the ictal discharge duration. Both synaptic and nonsynaptic mechanisms are important for the generation of ictal patterns of epileptiform activity. Although the synchronous epileptiform activity produced by pilocarpine required fast glutamate-mediated synaptic transmission, the transition from an interictal to ictal pattern of activity depended on [K+]o and could be influenced by extracellular space.

Picrotoxin-induced epileptiform activity in hippocampus: role of endogenous versus synaptic factors

1984 ◽  
Vol 51 (5) ◽  
pp. 1011-1027 ◽  
Author(s):  
J. J. Hablitz
Keyword(s):  
Refractory Period ◽  
Mossy Fiber ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Extracellular Recording ◽  
Synaptic Activity ◽  
Stratum Radiatum ◽  
Resting Membrane Potential ◽  
Stimulation Of

Picrotoxin-(PTX) induced epileptiform activity was studied in guinea pig hippocampal slices maintained in vitro, using intra- and extracellular recording techniques. The observed pattern of spontaneous and evoked epileptiform activity was quite complex. Spontaneous epileptiform events originated in the CA3 region and subsequently spread or propagated to CA1. Activation of CA1 could then reactivate CA3. This reverberation of activity was seen also following stimulation of the mossy fiber afferents from the dentate gyrus to CA3. Stimulation of fibers in the stratum radiatum of the CA1 region could trigger, at short latency, epileptiform activity that either was localized in CA1 or also occurred in CA3, with a late secondary discharge in CA1. This is attributed to a backfiring of the Schaffer collaterals and illustrates the ability of a variety of CA3 inputs to trigger epileptiform activity. Bath-applied PTX, at concentrations of 50-200 microM, had no apparent effect on the resting membrane potential or input resistance of the CA3 cells tested. Depolarizing current pulses elicited characteristic endogenous-burst responses that were not altered by PTX. Synaptic activity evoked by mossy fiber stimulation was altered markedly by PTX. The pattern of observed changes indicated that PTX reduced inhibitory postsynaptic potential (IPSP) amplitudes, resulting in the appearance of repetitive (presumably recurrent) excitatory inputs. Paroxysmal depolarizing shifts ( PDSs ) were generated by the coalescence of these excitatory inputs. Two types of spontaneous bursting were observed after PTX application. The first type was nonepileptiform , all or none in nature, and its frequency was voltage dependent. The second type of spontaneous burst was the PDS. It was epileptiform in character because it was associated with the synchronous discharge of many neurons. It was graded in nature, and its frequency was voltage independent. The graded nature of the PDS was demonstrated by varying the duration and intensity of the orthodromic stimulation. Trains of stimulation could produce PDSs that lasted 500-800 ms. A refractory period was observed following a PDS. By varying the strength of the orthodromic stimulation, it was possible to demonstrate that for the intervals tested this was a relative, not absolute, refractory period. Intracellular recordings in CA3 neurons indicated that each spontaneous PDS was followed by an afterhyperpolarization (AHP).

scholarly journals The effect of A1R agonist on epileptiform activity in organotypic slices

2020 ◽  
Author(s):  
Leonor Ribeiro Rodrigues ◽  
Dilip K. Tosh ◽  
Cláudia A Valente ◽  
Kenneth A. Jacobson ◽  
Joaquim A. Ribeiro ◽  
...  
Keyword(s):  
Side Effects ◽  
Ex Vivo ◽  
Epileptiform Activity ◽  
Neuronal Firing ◽  
Ex Vivo Model ◽  
A1 Adenosine Receptor ◽  
Cardiac Side Effects ◽  
Synchronous Firing ◽  
High K ◽  
Rhinal Cortex

Epilepsy is a common neurological disorder but resistance to pharmacotherapy makes it necessary the development of novel antiepileptic drugs (AEDs). An A1 adenosine receptor (A1R) agonist, MRS5474, possesses anticonvulsant activity in an animal model (Tosh et al.,2012-J.Med.Chem., 55,8075), without the cardiac side effects common to other A1R agonists, leading us to hypothesise that it could operate through a mechanism different from classical A1R agonists. We thus tested this hypothesis in an ex vivo model of epileptogenesis in rhinal cortex -hippocampus organotypic slices (Magalhães et al., 2018-J.Neuroinflam.15:203). MRS5474 (250nM) was incubated during 1h with slices under depolarizing ([K + ] o =8.5mM) or non-depolarizing ([K + ] o =3mM) conditions. Interestingly, MRS5474 decreased by 6615% (n=4, P<0.05) the number of bursts from slices under high K + but not under normal K + . Event frequency, amplitude and burst duration were not affected. The canonical A1R agonist, N 6 -cyclopentyladenosine (30nM, n=4) prevented burst-like activity (number of bursts decreased to zero, spike amplitude markedly reduced) even under non-depolarizing conditions. Our results showing that MRS5474 prevents spontaneous neuronal firing only under depolarizing conditions, suggest that it may predominantly influence spontaneous synchronous firing of stressed neurons, sparing non-injured ones. This renders this compound with presumably less side effects than other A1R agonists and currently available AEDs.

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