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83:3519-3524, 2000. ;J NeurophysiolZhi-Qi Xiong and Janet L. Stringerand Spreading DepressionGyrus During Electrical Stimulation, Seizure Discharges,Extracellular pH Responses in CA1 and the Dentate

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Extracellular pH Responses in CA1 and the Dentate Gyrus During

Electrical Stimulation, Seizure Discharges, and Spreading Depression

ZHI-QI XIONG AND JANET L. STRINGERDepartment of Pharmacology and Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Xiong, Zhi-Qi and Janet L. Stringer. Extracellular pH responses inCA1 and the dentate gyrus during electrical stimulation, seizuredischarges, and spreading depression. J Neurophysiol 83: 3519 3524,2000. Since neuronal excitability is sensitive to changes in extracel-lular pH and there is regional diversity in the changes in extracellularpH during neuronal activity, we examined the activity-dependentextracellular pH changes in the CA1 region and the dentate gyrus. Invivo, in the CA1 region, recurrent epileptiform activity induced bystimulus trains, bicuculline, and kainic acid resulted in biphasic pHshifts, consisting of an initial extracellular alkalinization followed bya slower acidification. In vitro, stimulus trains also evoked biphasic

pH shifts in the CA1 region. However, in CA1, seizure activity invitro induced in the absence of synaptic transmission, by perfusingwith 0 Ca2/5 mM K medium, was only associated with extracel-lular acidification. In the dentate gyrus in vivo, seizure activity in-duced by stimulation to the angular bundle or by injection of eitherbicuculline or kainic acid was only associated with extracellularacidification. In vitro, stimulus trains evoked only acidification. In thedentate gyrus in vitro, recurrent epileptiform activity induced in theabsence of synaptic transmission by perfusion with 0 Ca2/8 mM K

medium was associated with extracellular acidification. To testwhether glial cell depolarization plays a role in the regulation of theextracellular pH, slices were perfused with 1 mM barium. Bariumincreased the amplitude of the initial alkalinization in CA1 and causedthe appearance of alkalinization in the dentate gyrus. In both CA1 andthe dentate gyrus in vitro, spreading depression was associated with

biphasic pH shifts. These results demonstrate that activity-dependentextracellular pH shifts differ between CA1 and dentate gyrus both invivo and in vitro. The differences in pH fluctuations with neuronalactivity might be a marker for the basis of the regional differences inseizure susceptibility between CA1 and the dentate gyrus.

I N T R O D U C T I O N

Seizure activity is accompanied by rapid changes in the ioniccomposition of the extracellular space, including rises in ex-tracellular potassium concentration and changes in the extra-cellular pH. In contrast to the consistent increases in extracel-lular potassium during seizure activity, activity-dependent pH

changes are notable for their regional diversity (Chesler andKaila 1992; Deitmer and Rose 1996). In some structures, suchas adult spinal cord (Sykova and Svoboda 1990) and opticnerve (Davis et al. 1987), electrical stimulation induces apredominant extracellular acidification. In other regions, neu-ronal activity is accompanied by an initial extracellular alka-linization, followed by a slower acidification. Such early alka-line shifts have been reported in the cerebellum (Chesler and

Chan 1988; Kraig et al. 1983), cortex (Urbanics et al. 1978)and CA1 and CA3 regions of hippocampus (Jarolimek et al1989; Walz 1989). The functional significance and mechanisms underlying these regional dependant pH shifts are nowell understood.

There is evidence that neuronal excitability can be influenced by extracellular pH. The conductances of a variety of ionchannels are altered by shifts in pH (Baukrowitz et al. 1999Kiss and Korn 1999; Tombaugh and Somjen 1996), and thesechanges in conductance may modulate neuronal excitability. In

addition, both GABAA receptor current and N-methyl-D-aspartate (NMDA) receptor current are sensitive to extracellular pHExtracellular alkalosis decreases the conductance throughGABA

Areceptor channels (Pasternack et al. 1992) and in

creases the NMDA receptor-mediated current (Tang et al1990; Traynelis and Cull-Candy 1990). Therefore activitydependent extracellular pH shifts may be sufficient to affecneuronal excitability and the regional differences in activitydependent pH changes may underlie regional differences inseizure susceptibility. In view of the pH sensitivity of neuronaexcitability and regional diversity in the activity-dependent pHchanges, we compared the extracellular pH response duringseizure activity in the CA1 region and the dentate gyrus in vivoand in vitro.

M E T H O D S

In vivo recording

Adult Sprague-Dawley rats (150280 g, both sexes) were anesthetized with urethane (1.21.5 g/kg ip) and placed in a stereotaxic frameThe skull was exposed and burr holes drilled for electrode placementA concentric bipolar electrode was placed in the CA3 region of theleft hippocampus at an angle of 5 (AP, 3, ML, 3.5, depth 2.53.0mm). Another stimulating electrode, fashioned from 0.01-in diamTeflon-coated stainless steel wire, was placed in the right angulabundle (AP, 8, ML, 4.4, depth 2.53.5 mm). A double-barrel hydrogen-sensitive microelectrode was placed in CA1 or dentate gyru(lateral 1.21.8 mm) on the right side, in the same AP plane as theCA3 stimulating electrode. The animals were grounded through subcutaneous Ag/AgCl wire in the scapular region.

The hydrogen-sensitive microelectrodes were made according toestablished techniques (de Curtis et al. 1998). One barrel of thdouble-barreled electrode was silanized with 15% tri-N-butylchlorosilane (Alfrebro, Monroe, OH) in chloroform, and the tip was filled withthe hydrogen ionophore II (Fluka Cocktail A). The electrode was thenbackfilled with a buffer solution [(in mM): 100 NaCl, 10 HEPES, and10 NaOH, pH 7.5]. The reference barrel was filled with 2 M NaClThe electrode was calibrated before each experiment in a series ostandard solutions in artificial cerebrospinal fluid (ACSF; pH 6.08.0). The calibration solutions were similar to the ACSF, with

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NaHCO3

substituted for the corresponding moles of NaCl. The pH-sensitive microelectrodes had a response of 5560 mV for a unit pHchange. The extracellular field activity and pH signal were amplifiedand displayed on a chart recorder.

Administration of 20-Hz (300600 A, 0.3-ms biphasic pulses)stimulus trains every 15 min to the CA3 region or the angular bundlewere used to initiate seizure activity in CA1 or the dentate gyrus,respectively. At least five seizures were elicited in each recordinglocation, and the peak alkalinization and peak acidification weremeasured for each stimulus train. These measurements were averagedto produce a mean alkaline or acid peak change for that animal andthat stimulus/recording pair. Chemical convulsants, bicuculline andkainic acid, were used to initiate spontaneous epileptiform activity.Kainic acid (Sigma, St. Louis, MO) was dissolved in normal saline(0.9%) at 6 mg/ml and administrated intraperitoneally at a single doseof 12 mg/kg. ()Bicuculline (Sigma) was dissolved in 1 N HCl at 5mg/ml and was diluted to 0.5 mg/ml with normal saline just prior toinjection. Bicuculline was administrated intravenously at a dose of0.30.5 mg/kg, and the animal was monitored for 1020 min. Re-peated doses (up to 5) of bicuculline were administered to each animalat 1-h intervals. Each animal received either bicuculline or kainic acid,not both. For each animal receiving a chemical convulsant, recordingswere obtained from both CA1 and the dentate gyrus.

In vitro recording

Hippocampal slices were prepared by conventional methods fromSprague-Dawley rats (100200 g, both sexes). After anesthetizing therats (ketamine 25 mg/kg, xylazine 5 mg/kg, acepromazine 0.8 mg/kgip), the brains were removed. Transverse slices (400 500 m)through the hippocampus were cut with a Vibratome (TechnicalProducts International). Slices were placed in an interface-type cham-ber and continuously perfused with ACSF at 32C under a stream ofhumidified 95% O

2-5% CO

2. Composition of the ACSF was (in mM)

127 NaCl, 2 KCl, 1.5 MgCl, 1.1 KH2

PO4

, 26 NaHCO3

, 2 CaCl2

, and10 glucose. All solutions were bubbled constantly with 95% O

2-5%

CO2

. Slices were allowed to equilibrate for 1 h before electrophysi-ological recording was begun. A hydrogen-sensitive microelectrodewas placed in the cell body layer of CA1 or the dentate gyrus. A

bipolar tungsten stimulating electrode was positioned in the Schaffercollaterals to stimulate CA1 or the perforant path to stimulate thedentate gyrus. Stimulus trains (600 800 A, 0.3-ms biphasic pulsesat 15 Hz) were used to initiate synchronized neuronal activity in bothCA1 and the dentate gyrus.

Nonsynaptic epileptiform activity was induced in the hippocampusby changing to ACSF containing 0-added calcium and high potas-sium. The potassium was raised to 5 mM to induce epileptiformactivity in the CA1 region and was raised to 8 mM to induce epilep-tiform activity in the dentate gyrus. In both regions, this nonsynapticepileptiform activity can take more than 1 h to appear, but once itappears, the interval between field bursts and the burst durationremains stable for many hours (Bikson et al. 1999; Pan and Stringer1996).

R E S U L T S

pH changes in CA1 and dentate gyrus in vivo duringsynchronized neuronal activity

In urethan-anesthetized rats, 20-Hz stimulation of the CA3region or the angular bundle caused reproducible changes inthe extracellular field potential and extracellular pH in CA1and dentate gyrus (Fig. 1, n 12 animals). In the CA1pyramidal cell layer, stimulation was associated with a bipha-sic pH response. At the start of the stimulus train, the pH of theextracellular space became alkaline (0.050.1 pH units). This

was followed by an acidification (0.10.25 pH units). Aboveand below the pyramidal cell layer, the pH shifts were similarin shape to those recorded in the cell body layer. The magni-tude of the pH changes was maximal in the pyramidal cell layerand proximal dendrites and then gradually declined as threcording electrode was moved into stratum oriens or distal sradiatum and s. lacunosum-moleculare. Throughout the CA1region, the acidification peaked after termination of the stim-ulus train and after termination of the neuronal activity (Fig. 1and see Fig. 2A). In the dentate gyrus, stimulus trains to theangular bundle induced only acidification (Fig. 1, n 12animals) in the granule cell layer. The magnitude of the pHshift ranged from 0.2 to 0.3 pH units and was fairly constanfrom s. moleculare through the hilus. In contrast to CA1, in thedentate gyrus, the acidification peaked with the termination othe neuronal discharge (Fig. 2A).

To rule out the possibility that the difference in pH changesbetween CA1 and the dentate gyrus depended on the electricastimulation, the pH changes during spontaneous seizure

FIG. 1. Laminar profile of extracellular pH shifts in the hippocampus invivo. Stimulus trains were administered to the contralateral CA3 while ad

vancing a dual barrel (pH-sensitive and DC potential) electrode through thehippocampus. Shown are the extracellular pH changes at different laminae ohippocampus, indicated to the left. The vertical dashed lines mark the onset andtermination of the 20-Hz, 30-s stimulus trains. Horizontal dashed lines markthe extracellular pH baselines. Alkalinization is a downward change of the pHtracing, while acidification is an upward change.

3520 Z.-Q. XIONG AND J. L. STRINGER


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evoked by chemical convulsants were recorded. The pH re-sponses during spontaneous seizure activity induced by bicu-culline (0.3 mg/kg, n 6 animals) or kainic acid (12 mg/kg,n 3 animals) were similar to those evoked by stimulus trains.In CA1, the pH responses showed a biphasic pattern. At theonset of synchronized neuronal activity, marked by the nega-tive shift of the extracellular DC potential, there was an initialalkalinization similar to that recorded during stimulus trains.This alkalinization was followed by an acidification. The am-plitudes of the acidification and alkalinization were more vari-able than those seen during stimulation. In the dentate gyrus,only acidification was recorded (Fig. 2, B and C). The acidi-fication was only observed when there was synchronous dis-charge of the granule cells associated with a negative shift of

the DC potential.

pH responses in vitro

To further compare the pH responses in CA1 and the dentategyrus, we measured the extracellular pH changes in slices (Fig.3). The pH of the extracellular space in the slices was moreacidic than the perfusing solution (7.157.18 in the center ofthe slice compared with 7.357.40 in the perfusing solution)and there was a pH gradient across the thickness of the slice.This gradient was first reported in 1987 (Schiff and Somjen1987) and is now thought to be due to a gradient in pCO

2

(Chesler et al. 1994; Voipio and Kaila 1993). All the record-ings for the present study were obtained at the center of theslice (a depth of150 m). Stimulation of Schaffer collaterafibers (15 Hz, 30 s) evoked biphasic pH shifts in the CA1region similar to those recorded in vivo during stimulation(n 6 slices). Stimulation of synaptic inputs evoked only acidshifts in the dentate gyrus (n 6 slices). In both CA1 and thedentate gyrus, the extracellular space continued to acidify aftethe termination of the stimulus trains. But in the dentate gyrusthis poststimulus acidification was smaller than in CA1. Thesimilarity of the in vitro pH changes to those observed in vivosuggests that differences in blood flow between CA1 and thedentate gyrus are not an important contributor to the differenactivity-dependent pH patterns measured in vivo (Chesler and

Kaila 1992). However, the rate of recovery of the extracellulapH in vitro after the stimulus trains was significantly slower inboth CA1 and the dentate gyrus. For both CA1 and the dentategyrus, the mean half-time of recovery in vitro was 31.4 1.7(SE) s (n 6 for both CA1 and dentate gyrus), while in vivothe mean half-time of recovery was 9.7 0.6 s (n 6 for bothCA1 and dentate gyrus).

To test whether activity-dependent depolarization of gliacells may contribute to the extracellular pH changes in thhippocampus, extracellular pH was measured during stimulustrains in the presence of 1 mM barium (Fig. 3, n 6 slices, no

FIG. 2. Extracellular pH shifts during seizure activity. Field potential (f.p.) and extracellular pHchanges (pHo) in CA1 (left) and dentate gyrus (DGright) were recorded during synchronized neuronaactivity induced by 20-Hz stimulation (30 s, A) toCA3 for CA1 or angular bundle for dentate gyrusSimilar recordings are shown after intravenous injection of 0.3 mg/kg ()bicuculline (B). Chart recordings presented start seconds after the bicuculline injection. C: recordings 2 h after intraperitoneaadministration of 12 mg/kg kainic acid. After kainiacid, there are nearly continuous interictal dischargethat are not associated with detectable changes in pHChanges in extracellular pH corresponded with synchronized neuronal discharges, marked by the nega

tive shift of the DC potential. As in Fig. 1, alkalinization is represented by a negative change, whilacidification is a positive change.

352SEIZURE-INDUCED PH SHIFTS IN CA1 AND DENTATE GYRUS


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more than 1 slice from one animal). This concentration of

barium has been shown to block glial depolarization (Cheslerand Kraig 1989). In the presence of barium, the extracellularalkaline shifts were increased in CA1 from 0.04 0.01 pHunits before to 0.11 0.02 pH units after perfusion withbarium. In the dentate gyrus, barium caused the appearance ofan initial alkalinization (up to 0.09 pH units, range between0.06 and 0.13 pH units), so that the pH changes in the dentate

gyrus now resembled the pattern of changes normally recordedin CA1. The effects of barium were reversible.

To determine whether the extracellular pH changes duringsynchronized neuronal activity are due to synaptic transmission, we recorded the pH shifts during seizure activityinduced in nonsynaptic conditions (0-added calcium). Fieldbursts in CA1, induced by perfusion with 0-added Ca2 and5 mM K ACSF, were associated with acidification (Fig4A, n 6 slices). At the onset of the extracellular DC shiftindicating the onset of the synchronized neuronal burstthere was no alkalinization. After termination of the fieldburst, the extracellular pH began to recover toward baselinebut the onset of the next field burst caused acidificationagain. Field bursts in the dentate gyrus, induced by perfusion with 0-added Ca2 and 8 mM K ACSF, were associated only with acidification of the extracellular space (Fig4B, n 10 slices). As in CA1, the onset of the extracellularDC shift was associated with acidification. During the fieldburst, the extracellular pH appears to reach a plateau valueand then it recovers after termination of the field burst.

In some slices, spreading depression appeared spontaneously during perfusion with the 0-added calcium solution

(Fig. 5). In both CA1 and the dentate gyrus, the pH increasedat the onset of the spreading depression. This initial alkalinization was followed by a more sustained acidification tharecovered with the extracellular DC potential. To rule out thepossibility that residual calcium in the bath or in the extracellular space within the slice underlies the initial alkalinizationEGTA (1 mM, n 3 slices) or the calcium channel blockecadmium chloride (0.2 mM, n 3) was added to the 0-calciumACSF. Neither EGTA nor cadmium chloride blocked the alkaline shift in either CA1 or the dentate gyrus during spreadingdepression (data not shown).

D I S C U S S I O N

This study demonstrated that activity-dependent extracellular pH shifts differ between CA1 and the dentate gyrus. In theCA1 region, synchronized neuronal activity, induced by stimulus trains or chemical convulsants, was associated with bi-phasic pH shifts consisting of an extracellular alkalinizationfollowed by a slower acidification. In the dentate gyrus, syn-chronized neuronal activity was associated only with acidifi

FIG. 3. Stimulus evoked changes in extracellular pH in the hippocampalslice. Stimulus trains (15 Hz, 30 s) were alternately administrated to the CA3Schaffer collateral pathway or perforant path while measuring changes in pHin the pyramidal cell layer or granule cell layer, respectively. Top: stimulation-evoked pH changes in CA1 and the dentate gyrus in normal artificial cerebro-spinal fluid (ACSF). After addition 1 mM barium (middle), the alkaline shift inCA1 increased in amplitude and early alkaline response appeared in the dentategyrus. The effect of barium was reversible (wash). The vertical dashed linesmark the onset and termination of the 15-Hz, 30-s stimulus trains. Thehorizontal dashed lines mark the extracellular pH baseline. As in Fig. 1,alkalinization is represented by a negative change, while acidification is apositive change.

FIG. 4. pH responses during 0 Ca2/high K

induced nonsynaptic field bursts. A: simultaneourecordings of the f.p. and pHo in CA1 perfusedwith 0 Ca2/5 mM K medium. B: simultaneourecordings of the f.p. and pHo in the dentate gyruperfused with 0-Ca2/8 mM K medium. Dashedlines mark the extracellular pH baseline (The baseline level of extracellular pH of slices is 7.157.20The pH of perfusing ACSF is 7.35). As in Fig. 1alkalinization is represented by a negative changewhile acidification is a positive change.



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cation. In the absence of synaptic transmission, spontaneousepileptiform activity was associated with extracellular acidifi-cation in both CA1 and dentate gyrus. Initial alkalinizationfollowed by acidification was measured during spontaneousspreading depression in both CA1 and the dentate gyrus.

What is the cellular basis for the difference in extracel-

lular pH changes between CA1 and the dentate gyrus? Themain difference between the two regions is the presence ofthe initial alkalinization in CA1, which is absent in thedentate gyrus. Activity-dependent extracellular alkalineshifts have been linked to calcium influx into neurons. In theabsence of external calcium, the alkaline shifts are de-creased or completely blocked (Paalasmaa and Kaila 1996;Paalasmaa et al. 1994; Smith et al. 1994; Tong and Chesler1999). Consistent with this, the extracellular pH response inCA1 during epileptiform activity in nonsynaptic conditionsdisplayed only an acidification, suggesting that calciuminflux during synaptic transmission may underlie the alka-linization in CA1 (Chesler and Kaila 1992; Deitmer andRose 1996). But this does not explain the lack of alkalineshift in the dentate gyrus. Certainly during the stimulustrains in vivo and in vitro there is synaptic activity, which,presumably, is linked to calcium influx into neurons. Eitherthe mechanism linking calcium influx to extracellular alka-linization is not present in the dentate gyrus or the alkalin-ization is being neutralized by an overlapping acidificationthrough another mechanism.

Alkalinization of the extracellular space can occur in thedentate gyrus in vivo, at least during spreading depression(Somjen 1984). In vitro (present study), alkalinization associ-ated with spreading depression was present, even in the ab-

sence of external Ca2. Several questions remain to be answered. First, why are extracellular pH shifts similar in CA1and the dentate gyrus during spreading depression, but noduring synchronized neuronal activity? Why are the alkalineshifts abolished in 0 Ca2 medium during synchronized neuronal activity but not during spreading depression? So far wehave no explanations. Previous studies have indicated thaalkaline shifts can, in some instances, persist in the absence o

external Ca2

(Smith and Chesler 1999). Interestingly, it hasrecently been shown that the alkaline shift persists in thabsence of Ca2 during spreading depression induced byouabain and high-potassium (Menna et al. 1999). The datasuggest that the mechanisms underlying the pH shifts duringspreading depression are different from those active duringsynchronous neuronal activity.

Regional differences in glial function may explain the regional difference in pH regulation during neuronal activityDuring neuronal activity, potassium released from active neu-rons will depolarize glial cells, resulting in the net secretion oacid from the glia (Chesler and Kaila 1992). In the dentategyrus, this acid released from the glia may neutralize the initia

extracellular alkaline shift. Blockade of the glial depolarizationby barium (Ballanyi et al. 1987) would thus block the resultingsecretion of acid (Chesler and Kraig 1989; Grichtchenko andChesler 1994). This may unmask an alkalinization in thdentate gyrus, as has been shown in the dorsal horn of thespinal cord (Sykova et al. 1992). For this hypothesis to be trueone must propose regional differences in glial function between CA1 and the dentate gyrus. The density of the inwardrectifying potassium channels, which account for the activitydependent glial depolarization, has been shown to be lower inCA1 then in CA3 (DAmbrosio et al. 1998; McKhann et al1997), but glia in the dentate gyrus have not been studiedAlternatively, recent work has suggested that the effect o

barium may not be entirely due to the blockade of glial acidsecretion. Barium may substitute for calcium and movethrough calcium channels and in this way also contribute to thealkaline shifts (Smith and Chesler 1999)

The regional difference in the activity-dependent pH patterns between CA1 and the dentate gyrus during synchronizedneuronal activity may have important physiological significance. It has been shown that extracellular pH affects synaptictransmission and neuronal excitability. Since extracellular alkalosis decreases the conductance of GABA

Areceptor chan

nels (Pasternack et al. 1992) and increases the NMDA receptorcurrent (Tang et al. 1990; Traynelis and Cull-Candy 1990), theearly extracellular alkaline shift might increase (or sustainexcitability in the CA1 region prolonging the neuronal activityThe later acid shift might decrease the neuronal excitability andmay be involved in seizure termination in both CA1 and thedentate gyrus (Xiong et al. 2000). Therefore the differenextracellular pH patterns in CA1 and dentate gyrus maycontribute to the difference in their propensity for epilepticactivity.

This study was supported by National Institute of Neurological Disorderand Stroke Grant NS-39941 to J. L. Stringer.

Address for reprint requests: J. L. Stringer, Dept. of Pharmacology, BayloCollege of Medicine, One Baylor Plaza, Houston, TX 77030.

FIG. 5. pH responses during spreading depression in 0 Ca2/high K

media. A: simultaneous recordings of the f.p. and pHo during a singlespreading depression episode in CA1 perfused with 0 Ca2/5 mM Kmedium.

B: simultaneous recordings of the f.p. and pHo during a single spreadingdepression episode in the dentate gyrus perfused with 0 Ca2/8 mM K

medium. As in Fig. 1, alkalinization is represented by a negative change, whileacidification is a positive change.

352SEIZURE-INDUCED PH SHIFTS IN CA1 AND DENTATE GYRUS


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Received 6 January 2000; accepted in final form 6 March 2000.

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