Extracellular alkaline shifts in rat hippocampal slice are mediated by NMDA and non-NMDA receptors

Chen, J. C. T.; Chesler, Mitchell

doi:10.1152/jn.1992.68.1.342

Cited by 37 publications

(26 citation statements)

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“…Similarly in hippocampal slices, stimulation of the Schaffer collaterals produces an alkaline shift in CA1 extracellular space, sensitive to GLU antagonists (Chen and Chesler, 1992a,b). These external alkalinizations appear associated with postsynaptic receptor activation rather than neuronal firing (Chen and Chesler, 1992b;Chesler and Kaila, 1992). Displacement of H+ from internal binding sites by the GLUinduced increase in cytosolic Ca *+ constitutes a likely explanation for the initial GLU-induced accumulation of H+ .…”

Section: Discussionmentioning

confidence: 99%

Changes in intracellular pH associated with glutamate excitotoxicity

1993

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Excitotoxic neuronal injury is known to be associated with increases in cytosolic calcium ion concentrations. However, it is not known if perturbations in other intracellular ions are also associated with glutamate (GLU)-induced neuronal death. Accordingly, intracellular hydrogen ion concentrations were measured in cultured hippocampal neurons with the fluorescent dye BCECF during and after toxic exposures. Five minute GLU applications produced an initial cytosolic acidification. During the hour after GLU removal, intracellular pH (pHi) recovered steadily, resulting in a rebound cytosolic alkalinization. Lowering extracellular calcium depressed the initial GLU-induced acidification, suggesting that the rapid acidification may result partly as a consequence of calcium entry. An acidification- induced rebound alkalinization appeared to be activated by GLU exposure. Inhibitors of intracellular pH regulation, harmaline, 4,4′- disothiocyanatostilbene-2,2′-disulfonic acid (DIDS), and replacement of external Na+ with N-methyl-glucamine+ (NMG+), retarded the rate of recovery from GLU-induced acidification. The rapid acidification and rebound alkalinization could be mimicked by challenging neurons with elevated external K+ or replacement of external Na+ with NMG+. Two or more hours following toxic GLU exposure, hydrogen ion concentration did not stabilize at initial levels but progressively increased. High K+ or Na+ removal did not produce this long-term acidification and were not toxic. The cumulative increase in intracellular hydrogen ion may reflect the declining health of injured neurons and could contribute directly to neuronal death. Therefore, cytosolic acidification may act synergistically with increases in calcium concentration in mediating excitotoxicity.

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Section: Discussionmentioning

confidence: 99%

Changes in intracellular pH associated with glutamate excitotoxicity

1993

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“…Before the start of experiments the saline was switched to one with 0 MgCl 2 and 100 M picrotoxin. The absence of Mg 2ϩ and use of 3 mM Ca 2ϩ served to maximize the extracellular alkaline shifts (Chen and Chesler 1992a;Grichtchenko and Chesler 1996;Paalasmaa and Kaila 1996). This was necessary because of the extremely brief (20-ms) orthodromic stimulus train used to elicit rapid alkaline transients (see following text and DISCUSSION).…”

Section: Preparation and Solutionsmentioning

confidence: 99%

“…In a few experiments, alkaline shifts were induced by antidromic activation of the CA1 pyramidal neurons by stimulation of the alveus in the presence of picrotoxin, CNQX, and APV (Chen and Chesler 1992a). Methods for fabrication and calibration of the pH microelectrodes (tip diameter 4 -6 m) were the same as previously described (Chesler and Chan 1988), except that the reference barrel contained 150 mM NaCl, 2 mM HEPES (pH 7.3), and 0.5 M of a 2,000-kDa (mean weight) fluorescein-dextran (FD) conjugate (Molecular Probes D-7137).…”

Section: Electrical Stimulation and Recordingmentioning

confidence: 99%

Kinetics of Activity-Evoked pH Transients and Extracellular pH Buffering in Rat Hippocampal Slices

Tong¹,

Chen²,

Chesler³

2006

Journal of Neurophysiology

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Tong, Chi-Kun, Kevin Chen, and Mitchell Chesler. Kinetics of activity-evoked pH transients and extracellular pH buffering in rat hippocampal slice. J Neurophysiol 95: 3686 -3697, 2006. First published April 12, 2006 doi:10.1152/jn.01312.2005. The kinetics of activity-dependent, extracellular alkaline transients, and the buffering of extracellular pH (pH e ), were studied in rat hippocampal slices using a fluorescein-dextran probe. Orthodromic stimuli generated alkaline transients Յ0.05 pH units that peaked in 273 Ϯ 26 ms and decayed with a half-time of 508 Ϯ 43 ms. Inhibition of extracellular carbonic anhydrase (ECA) with benzolamide increased the rate of rise by 25%, doubled peak amplitude, and prolonged the decay three-to fourfold. The slow decay in benzolamide allowed marked temporal summation, resulting in a severalfold increase in amplitude during long stimulus trains. Addition of exogenous carbonic anhydrase reduced the rate of rise, halved the peak amplitude, but had no effect on the normalized decay. A simulation of extracellular buffering kinetics generated recoveries from a base load consistent with the observed decay of the alkaline transient in the presence of benzolamide. Under control conditions, the model approximated the observed decays with an acceleration of the CO 2 hydration-dehydration reactions by a factor of 2.5. These data suggest low endogenous ECA activity, insufficient to maintain equilibrium during the alkaline transients. Disequilibrium implies a time-dependent buffering capacity, with a CO 2 /HCO 3 Ϫ contribution that is small shortly after a base load. It is suggested that within 100 ms, extracellular buffering capacity is about 1% of the value at equilibrium and is provided mainly by phosphate. Accordingly, in the time frame of synaptic transmission, small base loads would generate relatively large changes in interstitial pH.

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“…1 A) (von Blankenfeld and Kettenmann, 1991). The K Ainduced acidification might be caused by influx of H ϩ down its electrochemical gradient through these cation channels (Chen and Chesler, 1992;Deitmer and Munsch, 1992). Another hypothesis is that an increase in intracellular Ca 2ϩ (Muller et al, 1992;Jabs et al, 1994;Munsch et al, 1994) activates a plasma membrane Ca 2ϩ /H ϩ -ATPase, extruding Ca 2ϩ in exchange for extracellular H ϩ ( Fig.…”

Section: /Hco 3 ϫ Cotransportmentioning

confidence: 99%

Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

1996

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The excitatory transmitter glutamate (Glu), and its analogs kainate (KA), andd-aspartate (d-Asp) produce significant pH changes in glial cells. Transmitter-induced pH changes in glial cells, generating changes in extracellular pH, may represent a special form of neuronal–glial interaction. We investigated the mechanisms underlying these changes in intracellular H+concentration ([H+]i) in cultured rat hippocampal astrocytes and studied their correlation with increases in intracellular Na+concentration ([Na+]i), using fluorescence ratio imaging with 2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) or sodium-binding benzofuran isophthalate (SBFI). Glu, KA, ord-Asp evoked increases in [Na+]i; Glu ord-Asp produced parallel acidifications. KA, in contrast, evoked biphasic changes in [H+]i, alkaline followed by acid shifts, which were unaltered after Ca2+removal and persisted in 0 Cl−-saline, but were greatly reduced in CO2/HCO−3-free or Na+-free saline, or during 4,4′-diisothiocyanato-stilbene-2,2′-disulphonic acid (DIDS) application. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked KA-evoked changes in [H+]iand [Na+]i, indicating that they were receptor–ionophore mediated. In contrast, CNQX increased the [H+]ichange and decreased the [Na+]ichange induced by Glu.d-Asp, which is transported but does not act at Glu receptors, induced [H+]iand [Na+]ichanges that were virtually unaltered by CNQX. Our study indicates that [Na+]iincreases are not primarily responsible for Glu- or KA-induced acidifications in astrocytes. Instead, intracellular acidifications evoked by Glu ord-Asp are mainly caused by transmembrane movement of acid equivalents associated with Glu/Asp-uptake into astrocytes. KA-evoked biphasic [H+]ichanges, in contrast, are probably attributable to transmembrane ion movements mediated by inward, followed by outward, electrogenic Na+/HCO−3cotransport, reflecting KA-induced biphasic membrane potential changes.

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Extracellular alkaline shifts in rat hippocampal slice are mediated by NMDA and non-NMDA receptors

Cited by 37 publications

References 0 publications

Changes in intracellular pH associated with glutamate excitotoxicity

Changes in intracellular pH associated with glutamate excitotoxicity

Kinetics of Activity-Evoked pH Transients and Extracellular pH Buffering in Rat Hippocampal Slices

Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

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Extracellular alkaline shifts in rat hippocampal slice are mediated by NMDA and non-NMDA receptors

Cited by 37 publications

References 0 publications

Changes in intracellular pH associated with glutamate excitotoxicity

Changes in intracellular pH associated with glutamate excitotoxicity

Kinetics of Activity-Evoked pH Transients and Extracellular pH Buffering in Rat Hippocampal Slices

Mechanisms of H+and Na+Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes

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Mechanisms of H⁺and Na⁺Changes Induced by Glutamate, Kainate, and d-Aspartate in Rat Hippocampal Astrocytes