Sodium-potassium pump inhibitors increase neuronal excitability in the rat hippocampal slice: role of a Ca2+-dependent conductance

1987 ◽  
Vol 57 (2) ◽  
pp. 496-509 ◽  
Author(s):  
M. McCarren ◽  
B. E. Alger
Keyword(s):  
Hippocampal Slice ◽  
Neuronal Excitability ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Extracellular Potassium ◽  
Gamma Aminobutyric Acid ◽  
Extracellular Potassium Concentration ◽  
Spike Threshold ◽  
Pump Activity ◽  
Voltage Dependent

We have used the rat hippocampal slice preparation as a model system for studying the epileptogenic consequences of a reduction in neuronal Na+-K+ pump activity. The cardiac glycosides (CGs) strophanthidin and dihydroouabain were used to inhibit the pump. These drugs had readily reversible effects, provided they were not applied for longer than 15-20 min. Hippocampal CA1 pyramidal cells were studied with intracellular recordings; population spike responses and changes in extracellular potassium concentration ([K+]o) were also measured in some experiments. This investigation focused on the possibility that intrinsic neuronal properties are affected by Na+-K+ pump inhibitors. The CGs altered the CA1 population response evoked by an orthodromic stimulus from a single spike to an epileptiform burst. Measurements of [K+]o showed that doses of CGs sufficient to cause bursting were associated with only minor (less than 1 mM) changes in resting [K+]o. However, the rate of K+ clearance from the extracellular space was moderately slowed, confirming that a decrease in pump activity had occurred. Intracellular recording indicated that CG application resulted in a small depolarization and apparent increase in resting input resistance of CA1 neurons. Although CGs caused a decrease in fast gamma-aminobutyric acid mediated inhibitory postsynaptic potentials (IPSPs), CGs could also enhance the latter part of the epileptiform burst induced by picrotoxin, an antagonist of these IPSPs. Since intrinsic Ca2+ conductances comprise a significant part of the burst, this suggested the possibility that Na+-K+ pump inhibitors affected an intrinsic neuronal conductance. CGs decreased the threshold for activation of Ca2+ spikes (recorded in TTX and TEA) without enhancing the spikes themselves, indicating that a voltage-dependent subthreshold conductance might be involved. The action of CGs on Ca2+ spike threshold could not be mimicked by increasing [K+]o up to 10 mM. A variety of K+ conductance antagonists, including TEA, 4-AP, Ba2+ (in zero Ca2+), and carbachol were ineffective in preventing the CG-induced threshold shift of the Ca2+ spike. The shift was also seen in the presence of a choline-substituted low Na+ saline. Enhancement of a slow inward Ca2+ current is a possible mechanism for the decrease in Ca2+ spike threshold; however, it is impossible to use the Ca2+ spike as an assay when testing the effects of blocking Ca2+ conductances. Therefore, we studied the influence of CGs on the membrane current-voltage (I-V) curve, since persistent voltage-dependent conductances appear as nonlinearities in the I-V plot obtained under current clamp.(ABSTRACT TRUNCATED AT 400 WORDS)

Cellular factors influencing GABA response in hippocampal pyramidal cells

1982 ◽  
Vol 48 (4) ◽  
pp. 938-951 ◽  
Author(s):  
R. K. Wong ◽  
D. J. Watkins
Keyword(s):  
Pyramidal Cells ◽  
Differential Sensitivity ◽  
Extracellular Potassium ◽  
Tetanic Stimulation ◽  
Gamma Aminobutyric Acid ◽  
Extracellular Potassium Concentration ◽  
Hyperpolarizing Response ◽  
Conductance Increase ◽  
Hippocampal Pyramidal Cells

1. The action of gamma-aminobutyric acid (GABA) on the hippocampal pyramidal cells was studied by intracellular recordings using an in vitro slice preparation. 2. Orthodromic tetanic stimulation induced dramatic modifications of the GABA response. Initial hyperpolarizing GABA responses were observed to invert to depolarizations following the tetanic shock. 3. The hyperpolarizing and depolarizing GABA responses exhibited differential sensitivity to GABA and bicuculline. Application of low concentrations of GABA predominantly activated the hyperpolarizing response. Activation of depolarizing response in both the dendrites and somata required a larger quantity of GABA. Bicuculline antagonized both the hyperpolarizing and depolarizing responses; however, the agent appeared to exert a stronger influence on the depolarizing response. At the concentration of 10(-5) M, bicuculline completely blocked the depolarizing response while the hyperpolarizing response was only suppressed by 50%. 4. During prolonged periods of GABA application (10 s or more), the GABA-induced conductance increase was not maintained, suggesting that the GABA response underwent desensitization. The results also suggest that the desensitization process affected both the hyperpolarizing and depolarizing responses. 5. The depolarizing response elicited by GABA was facilitated by increasing the extracellular potassium concentration. 6. It is possible that the modification of the GABA response following tetanic stimulation is in part caused by the desensitization of the GABA response and an accumulation of extracellular K+ and GABA.

Pharmacological mechanism of topiramate in the prophylaxis and treatment of migraine: a review

2018 ◽  
pp. 190-195
Author(s):  
Emanuela Paz Rosas ◽  
Raisa Ferreira Costa ◽  
Silvania Tavares Paz ◽  
Ana Paula Fernandes da Silva ◽  
Manuela Freitas Lyra de Freitas
Keyword(s):  
Cortical Spreading Depression ◽  
Molecular Mechanisms ◽  
Spreading Depression ◽  
Neuronal Excitability ◽  
Mechanisms Of Action ◽  
World Population ◽  
Gamma Aminobutyric Acid ◽  
Pharmacological Mechanism ◽  
Calcium Ion Channels ◽  
Voltage Dependent

Objective: This review sought to bring evidence of studies addressing the mechanisms of action of topiramate in the prevention and treatment of migraine. Background: Migraine is a neurovascular disorder that affects a large part of the world population. The use of prophylactics contributes to the decrease in the frequency and severity of this disease. Among the antiepileptic drugs, the topiramate, has proven to be the most effective for the treatment of migraine. Although the mechanism of action of this drug is still not well elucidated in the literature, there are several molecular mechanisms proposed. Methodology: A survey was carried out in the literature, from February to March 2018, in different databases, using the descriptors: topiramate, migraine and mechanisms of action. After a careful selection, 25 manuscripts were chosen for this review. Results: Evidence from a number of studies has indicated that the main mechanisms of action of topiramate are related to the modulation of voltage-dependent sodium and calcium ion channels, blockade of excitatory glutamate transmission and inhibition by gamma-aminobutyric acid receptors (GABA), AMPA/kainate and some isoenzymes of carbonic anhydrase. In addition, topiramate is involved in the suppression of cortical spreading depression, besides influencing trigeminovascular activity, and neuronal excitability. Conclusion: Thus, topiramate could be involved in the prevention of major events of the pathophysiology of migraine. Acting directly on cortical spreading depression (DAC), trigeminovascular signals and decreased central sensitization of migraine pain.

Epileptiform activity induced by low chloride medium in the CA1 subfield of the hippocampal slice

1990 ◽  
Vol 64 (6) ◽  
pp. 1747-1757 ◽  
Author(s):  
M. Avoli ◽  
C. Drapeau ◽  
P. Perreault ◽  
J. Louvel ◽  
R. Pumain
Keyword(s):  
Membrane Potential ◽  
Large Amplitude ◽  
Action Potentials ◽  
Hippocampal Slice ◽  
Epileptiform Activity ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Field Potentials ◽  
Maximal Amplitude

1. Extracellular and intracellular recordings and measurements of the extracellular concentration of free K+ ([K+]o) were performed in the CA1 subfield of the rat hippocampal slice during perfusion with artificial cerebrospinal fluid (ACSF) in which NaCl had been replaced with equimolar Na-isethionate or Na-methylsulfate (hereafter called low Cl- ACSF). 2. CAl pyramidal cells perfused with low Cl- ACSF generated intracellular epileptiform potentials in response to orthodromic, single-shock stimuli delivered in stratum (S.) radiatum. Low-intensity stimuli evoked a short-lasting epileptiform burst (SB) of action potentials that lasted 40–150 ms and was followed by a prolonged hyperpolarization. When the stimulus strength was increased, a long-lasting epileptiform burst (LB) appeared; it had a duration of 4–15 s and consisted of an early discharge of action potentials similar to the SB, followed by a prolonged, large-amplitude depolarizing plateau. The refractory period of the LB was longer than 20 s. SB and LB were also seen after stimulation of the alveus. 3. Variations of the membrane potential with injection of steady. DC current modified the shape of SB and LB. When microelectrodes filled with the lidocaine derivative QX-314 were used, the amplitudes of both SB and LB increased in a linear fashion during changes of the baseline membrane potential in the hyperpolarizing direction. The membrane input resistance, as measured by injecting brief square pulses of hyperpolarizing current, decreased by 65-80% during the long-lasting depolarizing plateau of LB. 4. A synchronous field potential and a transient increase in [K+]o accompanied the epileptiform responses. The extracellular counterpart of the SB was a burst of three to six population spikes and a small increase in [K+]o (less than or equal to 2 mM from a resting value of approximately 2.5 mM). The LB was associated with a large-amplitude, biphasic, negative field potential and a large increase in [K+]o (up to 12.4 mM above the resting value). Changes in [K+]o during the LB were largest at the border between S. oriens and S. pyramidale. This was also the site where the field potentials measured 2–5 s after the stimulus attained their maximal amplitude. Conversely, field potentials associated with the early component of the LB or with the SB displayed a maximal amplitude in the S. radiatum. 5. Spontaneous SBs and LBs were at times recorded in the CA1 and in the CA3 subfield.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of HCO3- ions in depolarizing GABAA receptor-mediated responses in pyramidal cells of rat hippocampus

1993 ◽  
Vol 69 (5) ◽  
pp. 1541-1555 ◽  
Author(s):  
L. M. Grover ◽  
N. A. Lambert ◽  
P. A. Schwartzkroin ◽  
T. J. Teyler
Keyword(s):  
Gabaa Receptor ◽  
Gabab Receptor ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Gamma Aminobutyric Acid ◽  
Free Medium ◽  
Postsynaptic Potentials ◽  
Ca1 Pyramidal Cells ◽  
Ionic Basis

1. Activation of GABAA receptors can produce both hyperpolarizing and depolarizing responses in CA1 pyramidal cells. The hyperpolarizing response is mediated by a Cl- conductance, but the ionic basis of the depolarizing response is not clear. We compared the GABAA receptor-mediated depolarizations induced by synaptically released gamma-aminobutyric acid [GABA; depolarizing inhibitory postsynaptic potentials (dIPSPs)] with those produced by exogenous GABA (depolarizing GABA responses). Short trains of high-frequency (200 Hz) stimuli were used to generate dIPSPs. We found that dIPSPs generated by trains of stimuli and depolarizing responses to exogenous GABA were accompanied by a conductance increase and had a similar reversal potential, indicating a similar ionic basis for both responses. 2. We wished to determine whether an HCO3- current contributed to the GABAA-mediated depolarizations. We found that dIPSPs and depolarizing GABA responses were sensitive to perfusion with HCO3(-)-free medium. Interpretation of these data was complicated by the mixed nature of the responses: dIPSPs were invariably accompanied by conventional, Cl(-)-mediated fast hyperpolarizing IPSPs (fIPSPs), and response to exogenous GABA usually consisted of biphasic hyperpolarizing and depolarizing responses. However, it was sometimes possible to elicit responses to GABA that appeared purely depolarizing (monophasic depolarizing GABA responses). 3. We analyzed monophasic depolarizing GABA responses and found no change in reversal potential when slices were perfused with HCO(3-)-free medium. We also made whole-cell recordings from CA1 pyramidal cells, attempting to reduce [HCO3-]i, and compared the reversal potential for monophasic depolarizing GABA responses with similar responses recorded with fine intracellular microelectrodes. We found no difference in reversal potential. We also examined effects of the carbonic anhydrase inhibitor acetazolamide (ACTZ) on depolarizing GABA responses. ACTZ reduced these responses but did not change their reversal potential. 4. Effects of HCO(3-)-free medium were not specific to GABAA receptor-mediated responses. GABAB receptor-mediated slow IPSPs (sIPSPs) were also reduced, as were excitatory postsynaptic potentials (EPSPs). Analyses of field potentials and spontaneous fIPSPs suggested a decrease in presynaptic excitability during perfusion with HCO(3-)-free medium. In addition, pyramidal cells showed decreased input resistance when perfused with HCO(3-)-free medium. 5. The sensitivity of GABAA receptor-mediated depolarizations to HCO(3-)-free medium can be explained by a decrease in presynaptic excitability and an increased resting conductance in postsynaptic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Carbachol-induced synchronized rhythmic bursts in CA3 neurons of guinea pig hippocampus in vitro

1994 ◽  
Vol 72 (1) ◽  
pp. 131-138 ◽  
Author(s):  
R. Bianchi ◽  
R. K. Wong
Keyword(s):  
Membrane Potential ◽  
Guinea Pig ◽  
Mossy Fiber ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Gamma Aminobutyric Acid ◽  
Action Potential Firing ◽  
Potential Firing

1. Carbachol effects on CA3 hippocampal cells were studied in the absence of ionotropic glutamatergic and GABAergic transmission with intracellular and extracellular recordings from guinea pig septohippocampal slices. 2. In all experiments the perfusing solution contained ionotropic glutamate and gamma-aminobutyric acid (GABA) receptor blockers [6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10–20 microM), 3-((+/-)-2-carboxypiperazin-4-il)propyl-1-phosphonic acid (CPP, 10–20 microM), and picrotoxin (50 microM), respectively]. Under these conditions, the excitatory and early inhibitory postsynaptic potentials, evoked in CA3 pyramidal cells by mossy fiber stimulation before the addition of the blockers, were completely suppressed. 3. Carbachol (50 microM) introduced via bath perfusion or pulse application elicited a series of rhythmic bursts with overriding action potentials. Each rhythmic burst lasted up to 30 s and repeated at intervals of 0.7–6 min. Rhythmic bursts were blocked by atropine (1 microM). 4. At membrane potentials more depolarized than -70 mV, carbachol also elicited a sustained depolarization associated with an increase in membrane input resistance and action-potential firing. This response was blocked by atropine (1 microM). 5. Carbachol can induce both rhythmic bursts and sustained depolarizations in the same cell. Rhythmic bursts were elicited when the membrane potential of the cell was more hyperpolarized than -70 mV; sustained depolarizing responses were activated by carbachol when the cell membrane potential was more depolarized than -70 mV. 6. Extracellular field potential responses in the CA3 region occurred simultaneously with rhythmic bursts, indicating the synchronization of the event in the CA3 field. Dual intracellular recordings confirmed that rhythmic bursts occurred simultaneously in CA3 hippocampal pyramidal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells

2004 ◽  
Vol 76 (4) ◽  
pp. 475-480 ◽  
Author(s):  
Rainer Surges ◽  
Thomas M. Freiman ◽  
Thomas J. Feuerstein
Keyword(s):  
Pyramidal Cells ◽  
Input Resistance ◽  
Ca1 Pyramidal Cells ◽  
Voltage Dependent

Intracellular pH changes produced by glutamate uptake in rat hippocampal slices

1994 ◽  
Vol 72 (4) ◽  
pp. 1686-1696 ◽  
Author(s):  
A. Amato ◽  
L. Ballerini ◽  
D. Attwell
Keyword(s):  
Intracellular Ph ◽  
Chloride Channels ◽  
Glutamate Uptake ◽  
Hippocampal Slices ◽  
Disulfonic Acid ◽  
Extracellular Potassium ◽  
Gamma Aminobutyric Acid ◽  
Extracellular Potassium Concentration ◽  
Ph Changes ◽  
Glutamate Concentration

1. The mean intracellular pH in area CA1 of rat hippocampal slices was monitored fluorescently after loading the cells with the dye BCECF-AM. 2. Including L-glutamate in the solution superfusing the slice led to the intracellular pH becoming more acid. This acidification had a roughly Michaelis-Menten dependence on the superfused glutamate concentration with a half-maximal dose around 200 microM: this value must overestimate the glutamate concentration at most of the cells, which will be reduced by uptake. 3. The glutamate-evoked acidification was not significantly reduced by blockers of glutamate-gated ion channels [6-cyano-7-nitroquinoxaline-2,3- dione (CNQX) and D-aminophosphonovalerate (APV)] nor by blockers of gamma-aminobutyric acid (GABA)- and glycine-gated channels (picrotoxin and strychnine), and so was not produced by H+ entry through alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptor channels nor by HCO3- exit through the chloride channels controlled by GABA or glycine. 4. The glutamate-evoked acidification was not reduced by tetrodotoxin (TTX), ruling out the possibility of it being generated by action potentials. It was also unaffected by saturation of presynaptic L-amino-4-phosphonobutanoate (AP4) receptors with AP4. 5. In the presence of blockers of glutamate-, GABA-, and glycine-gated channels, the acidification showed the pharmacology of glutamate uptake and was reduced by a glutamate uptake blocker. 6. The glutamate-evoked acidification showed an ion dependence similar to that of glutamate uptake. It was abolished by removal of extracellular sodium and was reduced by raising the extracellular potassium concentration. It was unaffected by blockers of Na+/H+ exchange (amiloride) and Na+/HCO3- cotransport [4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)] and so was not produced by the Na+ influx accompanying glutamate uptake changing the activity of these carriers. 7. These data show that the glutamate uptake carrier acidifies hippocampal cells, possibly because it transports a pH-changing anion out of the cell as in salamander glial cells. Glutamate uptake may thus contribute to activity-induced pH changes in the nervous system.

Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih

2016 ◽  
Vol 26 (08) ◽  
pp. 1650044 ◽  
Author(s):  
Lihua Wang ◽  
Suzie Dufour ◽  
Taufik A. Valiante ◽  
Peter L. Carlen
Keyword(s):  
Neuronal Excitability ◽  
Seizure Activity ◽  
Membrane Properties ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Hcn Channels ◽  
Extracellular Potassium Concentration ◽  
Prolonged Seizure

Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP). However, when [K[Formula: see text]]o reached higher than 9[Formula: see text]mM, seizure like events (SLEs) were blocked and neurons went into a depolarization-blocked state. Spreading depression was never observed as the blockade of ictal events could be reversed within 1–2[Formula: see text]min after the raised [K[Formula: see text]]o was changed back to control levels. This concentration-dependent dual effect of [K[Formula: see text]]o was observed using in vivo and in vitro mouse brain preparations as well as in human neocortical tissue resected during epilepsy surgery. Blocking the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, modulated the elevated [K[Formula: see text]]o influence on SLEs by promoting the high [K[Formula: see text]]o inhibitory actions. These results demonstrate biphasic actions of raised [K[Formula: see text]]o on neuronal excitability and seizure activity.

Use-dependent depression of IPSPs in rat hippocampal pyramidal cells in vitro

1985 ◽  
Vol 53 (2) ◽  
pp. 557-571 ◽  
Author(s):  
M. McCarren ◽  
B. E. Alger
Keyword(s):  
Membrane Potential ◽  
Conditioning Stimulus ◽  
Pyramidal Cells ◽  
Repetitive Stimulation ◽  
Stratum Radiatum ◽  
Resting Potential ◽  
Masking Effect ◽  
Extracellular Potassium ◽  
Gamma Aminobutyric Acid ◽  
Hippocampal Pyramidal Cells

We have used intracellular recording techniques to study the use-dependence of evoked inhibitory postsynaptic potentials (IPSPs) in rat CA1 hippocampal pyramidal cells. We determined reversal potentials and conductance changes associated with IPSPs and responses to directly applied gamma-aminobutyric acid (GABA). The IPSP depression could be seen after a single conditioning stimulus. This depression appeared to be due primarily to a 50% decrease in IPSP conductance (gIPSP). Trains of stimulating pulses (50 pulses at 5 or 10 Hz) produced more pronounced effects than a single conditioning pulse. Suprathreshold repetitive stimulation of stratum radiatum (SR) produced epileptiform burst firing and greater depression of IPSPs than did alvear (ALV) or subthreshold SR stimulation. During suprathreshold SR stimulation the IPSP was nearly abolished and the membrane potential could become less negative than the resting potential. A masking effect of facilitated depolarizing potentials on IPSPs was unlikely since IPSPs accompanied by little or no depolarizing potential were also depressed by SR trains. The 75% reduction in IPSP conductance found after repetitive stimulation confirmed that an overlapping conductance was not responsible for the depression of the IPSP. The GABA-induced conductance increase was not depressed by identical trains. Trains of stimulation induced depolarizing shifts in equilibrium potentials for the IPSP (EIPSP) and GABA (EGABA) of approximately 10 mV. These shifts were always greater after SR trains than after ALV trains. Simultaneous recordings of membrane potential and extracellular potassium concentration ([K+]o) with K+-sensitive microelectrodes revealed a direct correlation between the two during a stimulus train. Membrane potential depolarized as much as 18 mV from the peak of the IPSP and [K+]o could increase to a maximum of 10 mM during some trains. A depressant effect (of approximately 50%) of K+ on IPSPs was demonstrated by brief pressure ejection of K+ near the soma. We conclude that repetitive stimulation depresses gIPSP and shifts EIPSP in the depolarizing direction. Whereas gIPSP began to decline after a single conditioning pulse, the additional depression of IPSPs produced by stimulus trains was due in large part to shifts in EIPSP. Depression of gIPSP was not due to desensitization or block of ionic conductances, since gGABA was not reduced. The EIPSP may change as a result of increases in [K+]o.

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