Electrophysiological properties of rat CA1 pyramidal neurones in vitro modified by changes in extracellular bicarbonate.

Church, John A.; McLennan, H.

doi:10.1113/jphysiol.1989.sp017713

Cited by 52 publications

(65 citation statements)

References 40 publications

(78 reference statements)

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“…We developed a technique to measure [Ca 2ϩ ] i , pH i , and V m simultaneously in cultured hippocampal neurons and used it to substantiate and extend previous findings, made on the basis of electrophysiological recordings from CA1 pyramidal neurons in slices (Church 1992(Church , 1999Church and McLennan 1989;Kelly and Church 2004), that the slow AHP is modulated by changes in pH o and pH i . Although changes in pH i at a constant pH o were able to modulate the slow AHP in the absence of marked changes in [Ca 2ϩ ] i transients, inhibition of the slow AHP by decreases in pH o was not dependent on reductions in pH i but rather reflected a low pH o -dependent reduction in the priming Ca 2ϩ signal.…”

Section: Discussionmentioning

confidence: 85%

“…Reductions in pH, for example, may contribute to the inhibition of the slow AHP observed during oxygen deprivation (Kulik et al 2002) and, if pronounced, may in this way promote neuronal injury. Conversely, an increase in the slow AHP may help to limit the increases in neuronal excitability and epileptiform activity observed during increases in pH (Balestrino and Somjen 1988;Church and McLennan 1989;also Kelly and Church, unpublished observations), especially if Ca 2ϩ influx is increased to such an extent that the underlying channels become saturated (see Canepari et al 2000;Sinha et al 1995). The present results also raise the possibility that activity-induced reductions in pH o/i could limit the potential therapeutic effects of agents designed to enhance the slow AHP, and it will be important to assess whether such agents, like the neuronal SK channel enhancer EBIO (Peitersen et al 2006; see also Pedarzani et al 2005), retain their ability to augment the slow AHP at the low pH values associated with pathological events such as ischemia.…”

Section: Functional Implicationsmentioning

confidence: 99%

“…Although the molecular correlate of the apamin-insensitive Ca 2ϩ -activated K ϩ current that underlies the slow AHP (sI ahp ) remains unknown, it is apparent that it can be modulated by a large number of neurotransmitters and second-messenger systems (reviewed by Vogalis et al 2003;see also Stocker 2004). The slow AHP and sI ahp are also sensitive to changes in extracellular pH (pH o ); decreases and increases in pH o inhibit and augment, respectively, sI ahp and the slow AHP, with consequent effects on neuronal excitability (Church 1999;Church and McLennan 1989;Kelly and Church 2004). Nevertheless, the relative contributions of changes in the priming Ca 2ϩ signal and intracellular pH (pH i ) to the modulation of sI ahp and the slow AHP by changes in pH o remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Relationships Between Calcium and pH in the Regulation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Neurons

Kelly

Church²

2006

Journal of Neurophysiology

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The Ca2+-dependent slow afterhyperpolarization (AHP) is an important determinant of neuronal excitability. Although it is established that modest changes in extracellular pH (pHo) modulate the slow AHP, the relative contributions of changes in the priming Ca2+ signal and intracellular pH (pHi) to this effect remain poorly defined. To gain a better understanding of the modulation of the slow AHP by changes in pHo, we performed simultaneous recordings of intracellular free calcium concentration ([Ca2+]i), pHi, and the slow AHP in cultured rat hippocampal neurons coloaded with the Ca2+- and pH-sensitive fluorophores fura-2 and SNARF-5F, respectively, and whole cell patch-clamped using the perforated patch technique. Decreasing pHo from 7.2 to 6.5 lowered pHi, reduced the magnitude of depolarization-evoked [Ca2+]i transients, and inhibited the subsequent slow AHP; opposite effects were observed when pHo was increased from 7.2 to 7.5. Although decreases and increases in pHi (at a constant pHo) reduced and augmented, respectively, the slow AHP in the absence of marked changes in preceding [Ca2+]i transients, the inhibition of the slow AHP by decreases in pHo was correlated with low pHo-dependent reductions in [Ca2+]i transients rather than the decreases in pHi that accompanied the decreases in pHo. In contrast, high pHo-induced increases in the slow AHP were correlated with the accompanying increases in pHi rather than high pHo-dependent increases in [Ca2+]i transients. The results indicate that changes in pHo modulate the slow AHP in a manner that depends on the direction of the pHo change and substantiate a role for changes in pHi in modulating the slow AHP during changes in pHo.

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Section: Discussionmentioning

confidence: 85%

Section: Functional Implicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Relationships Between Calcium and pH in the Regulation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Neurons

Kelly

Church²

2006

Journal of Neurophysiology

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“…387 Carbonic anhydrase in astrocytes also can influence neuronal excitability by regulating extracellular pH. Decreasing pH tends to depress epileptiform burst firing, through a variety of actions, 388 including effects on NMDA receptors, which are inhibited by extracellular H ϩ . 389 Acetazolamide and various related sulfamates were shown in the 1950s to inhibit carbonic anhydrase and to be anticonvulsant in rodent seizure models (more effective against MES than against PTZ seizures) and in humans against generalized and focal motor seizures and absence epilepsy.…”

Section: Carbonic Anhydrasementioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…The latter appears to be the predominant mechanism in several different types of mammalian central neurones (Lux, Loracher & Neher, 1970;Llinas, Baker & Precht, 1974;Raabe & Gumnit, 1975;Misgeld, Deisz, Dodt & Lux, 1986;Thompson, Deisz & Prince, 1988a, b;Thompson & Giihwiler, 1989) and in other neural preparations (Russel & Brown, 1972;Nicoll, 1978;Scappaticci, Dretchen, Carpenter & Pellmar, 1981;Aickin, Deisz & Lux, 1982;Altamirano & Russell, 1987). The outward movement of Cl-is considered to be coupled to K+ (Aickin et al 1982), but a HCO3--Cl-exchange cannot be excluded (Church & McLennan, 1989;Russell & Boron, 1990). If an outward transport system exists in these immature CAl neurones, activation of the outward Cl-transport will cause a net efflux of Cl-ions against the electro-chemical gradient, and move EGABA or EIPSP towards a more negative potential.…”

Section: Gaba Inhibition In Immature Cai Neuronesmentioning

confidence: 99%

Development of GABA‐mediated, chloride‐dependent inhibition in CA1 pyramidal neurones of immature rat hippocampal slices.

Zhang

Spigelman

Carlen

1991

The Journal of Physiology

176

102

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SUMMARY1. y-Aminobutyric acid (GABA)-mediated, Cl--dependent inhibitory postsynaptic potentials (IPSPs) and GABA currents in immature rat hippocampal CAI neurones were studied using the whole-cell recording technique in brain slices.2. IPSPs evoked by electrical stimulation were observed in postnatal 2-to 5-(PN2-5), 8-to 13-(PN8-13) and 15-to 20-(PN15-20)day-old CAI neurones. In the presence of glutamate receptor blockers 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D-2-amino-5-phosphonovaleric acid (APV), the reversal potential for the IPSP (ElPSP) was near the resting membrane potential (RMP) in the PN2-5 neurones, but 13 and 25 mV more negative than the RMP in PN8-13 and PN15-20 neurones respectively. IPSPs and GABA currents were blocked by the GABAAreceptor antagonists bicuculline or picrotoxin.3. The reversal potential for somatic GABA currents (EGABA) was examined in the presence of tetrodotoxin (TTX). There was a strong dependence of the EGABA upon the patch pipette [Cl-] ([CI-]p), indicating that the GABA currents were mediated by a Cl-conductance. In PN2-5 neurones, EGABA agreed with the value predicted by the Goldman-Hodgkin-Katz equation at given concentrations of internal and external anions permeable through GABA-activated Cl-channels, whereas EGABA in older neurones was 8-18 mV more negative.4. Examination of the relations between EGABA, holding potential, [Cl-]p and resting conductance indicated that the membrane of the PN2-5 neurones was readily permeable to Cl-which followed a passive Donnan equilibrium. Passive distribution of Cl-played a decreasing role in PN8-13 neurones and in PN1S-20 neurones.5. To assess the contribution of outward Cl-co-transport, bath applications of high K+ or furosemide were performed. High K+ and furosemide caused a reversible positive shift of EGABA in PN15-20 neurones. Raising the temperature moved EGABA to a more negative potential, with a Qlo of 5 mV. A similar change of EGABA in response to high K+, but not to furosemide, was found in PN8-13 neurones.6. The present data indicate the existence of GABAA-mediated inhibitory synaptic connections in CAI neurones at the earliest stages of postnatal life. During the first postnatal week, Cl-ions are passively distributed and the EIPSP and EGABA NS 9102 L. ZHANG, I. SPIGELMAN AND P. L. CARLEN are near the RMP. After the first postnatal week, EIPSP and EGABA move to potentials more negative than the RMP, partly due to the gradual development of Cl-extrusion system(s), thereby maintaining a driving force for hyperpolarizing IPSPs at the resting potential in the more mature neurones.

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Electrophysiological properties of rat CA1 pyramidal neurones in vitro modified by changes in extracellular bicarbonate.

Cited by 52 publications

References 40 publications

Relationships Between Calcium and pH in the Regulation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Neurons

Relationships Between Calcium and pH in the Regulation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Neurons

Molecular Targets for Antiepileptic Drug Development

Development of GABA‐mediated, chloride‐dependent inhibition in CA1 pyramidal neurones of immature rat hippocampal slices.

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