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The Journal of Neuroscience, February 15, 2000, 20(4):1290-1296
Activity-Dependent Intracellular Acidification Correlates with
the Duration of Seizure Activity
Zhi-Qi
Xiong1,
Peter
Saggau2, and
Janet L.
Stringer1, 2
1 Department of Pharmacology and 2 Division
of Neuroscience, Baylor College of Medicine, Houston, Texas
77030
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ABSTRACT |
Synchronized neuronal activity (seizures) can appear in the
presence or absence of synaptic transmission. Mechanisms of seizure initiation in each of these conditions have been studied, but relatively few studies have addressed seizure termination. In particular, how are seizures terminated in the absence of synaptic activity where there is no loss of excitatory drive or augmentation of
inhibitory inputs? We have studied dynamic activity-dependent changes
of intracellular pH in the absence of synaptic transmission using the
fluorescent pH indicator carboxylseminaphthorhodafluo-1. During
epileptiform activity we observed intracellular acidification, whereas
between seizures the intracellular pH recovered. Experimental conditions that shortened the epileptiform discharge correlated with
more rapid intracellular acidification. On the other hand, experimental
manipulation of intracellular pH altered the duration of the seizure
discharge, with acidification resulting in early termination of the
epileptiform activity. These data show a direct relationship between
the level of intracellular acidification and the duration of the
seizures, suggesting that an intracellular pH-dependent process can
terminate nonsynaptic neuronal synchronization.
Key words:
intracellular pH; seizure termination; dentate gyrus; SNARF-1; hippocampus; neuronal synchronization
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INTRODUCTION |
Epilepsy is characterized by the
periodic and unpredictable occurrence of seizures, which are clinically
defined as transient behavioral changes attributable to the synchronous
and rhythmic firing of populations of neurons in the CNS. The
cellular mechanisms involved in the generation and termination of
seizures are not well understood. Much basic research has focused on
the mechanisms of seizure initiation. Relatively few studies have
addressed how seizures terminate (Konnerth et al., 1986 ; Spencer and
Spencer, 1996; Bragin et al., 1997). Understanding factors critical for terminating an ongoing seizure may lead to more effective treatment of epilepsy.
Neuronal activity elicits substantial changes in extracellular and
intracellular pH in both pathological states and during normal brain
function (Chesler and Kaila, 1992; Zhan et al., 1998; Tong and Chesler,
1999). During seizure activity neurons accumulate H+, resulting in acidification of the
intracellular space. The pH of the extracellular space also decreases
during seizure activity, often after a transient alkaline shift
(Siesj et al., 1985; Tomlinson et al., 1992; Velisek et al., 1994; de
Curtis et al., 1998; Gutschmidt et al., 1999). The physiological
significance of these pH shifts during seizure activity is not known.
On the basis of the marked pH sensitivity of many ion channels,
enzymes, and even receptors (Tang et al., 1990; Gottfried and Chesler,
1994; Tombaugh and Somjen, 1996; Baukrowitz et al., 1999; Kiss and
Korn, 1999; Qu et al., 1999; Vincent et al., 1999), it has been
suggested that pH shifts associated with neuronal activity serve as
local feedback signals (Ransom, 1992; Gottfried and Chesler, 1994;
Tombaugh and Somjen, 1996). There are a few studies analyzing the
interaction of extracellular pH and epileptiform activity, but data
correlating intracellular pH (pHi) and neuronal
activity are still missing (Chesler and Kaila, 1992; Velisek et al.,
1994; Bonnet et al., 1998; de Curtis et al., 1998).
The currently available methods for measuring pHi
include pH-sensitive microelectrodes, 31P
NMR spectroscopy, and pH-sensitive fluorescence probes
(Tsien, 1989). We used carboxylseminaphthorhodafluo-1 (SNARF-1), a
single-excitation, dual-emission fluorescent pH indicator (Tsien, 1989;
Muller-Borer et al., 1998; Roberts, 1999), to study the interaction
between pHi and seizure onset and termination.
Fluorescence microscopy with pH-sensitive fluorophores allows
pHi changes to be measured with temporal and
spatial resolutions that surpass microelectrodes or NMR, respectively
(Muller-Borer et al., 1998). We chose an in vitro model of
nonsynaptic seizure activity in the dentate gyrus, induced by perfusing
hippocampal slices with a low-Ca2+,
high-K+ solution. The epileptiform
activity consists of bursts of large-amplitude population spikes,
termed field bursts (Schweitzer et al., 1992; Pan and Stringer, 1996).
These field bursts persist in the presence of blockers of both
excitatory and inhibitory neurotransmission (Schweitzer et al., 1992).
The spontaneous field bursts recur in a regular pattern, are of long
duration, and are associated with extracellular ionic changes. These
features provide a well suited in vitro model to study the
relationship of changes in pHi and the
epileptiform discharges.
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MATERIALS AND METHODS |
Preparation of hippocampal slices and solutions.
Transverse hippocampal slices (350-400 µm) were prepared from
Sprague Dawley rats (28-35 d old) as described (Pan and Stringer,
1996). All experimental procedures were approved by the Animal Research
Committee of Baylor College of Medicine. Brain slices were stored in
artificial CSF (ACSF; in mM): NaCl 127, KCl 2, MgSO4 1.5, KH2PO4 1.1, NaHCO3 26, CaCl2 2, and
D-glucose 10, saturated with 95% O2
and 5% CO2 to maintain a constant pH of 7.38. Slices were allowed to recover for 1 hr from their dissection before
indicator loading. Field bursts were induced by switching the perfusing
solution to ACSF with 0 added Ca2+ and 8 mM K+. When sodium propionate
or ammonium chloride was added to the perfusing solution, the NaCl
concentration was reduced by equimolar amounts. For local application
of acidic medium, 0 added Ca2+ and 8 mM K+ medium was acidified by
HCl to pH 6.0 and was applied locally by leakage from a glass pipette
(tip diameter, 2-3 µm) lowered into the slice.
SNARF-1 loading. The AM of the pH indicator SNARF-1
(50 µg) was dissolved in 20 µl of DMSO containing 10% pluronic
acid (w/w). The dissolved indicator was further diluted by 2 ml of
ACSF, giving a final concentration of SNARF-1 AM of 40 µM. This solution, with four or five brain slices, was
then put into a 35 mm Petri dish, which served as the loading chamber.
The dish was then covered and placed in a 30°C water bath for 3 hr.
The membrane-permeable indicator is taken up into cells where it is
hydrolyzed by an endogenous esterase. The resulting free acid is
retained in the cells.
Optical recording. After indicator loading, brain slices
were placed for 5-10 min in a large volume (200 ml) of ACSF,
equilibrated with O2 and
CO2, to remove indicator from the extracellular
space. Individual slices were then placed in the interface chamber
mounted on an upright epifluorescence microscope (Zeiss) and
perfused with ACSF for 30 min. A tungsten lamp (100 W; Osram Sylvania) driven by a stabilized power supply was used as the light source. To
prevent condensation from the humidified atmosphere on the objective,
we externally heated the objective to ~45°C. An area of 80-120
µm in diameter in the cell body layer of the dentate gyrus was
illuminated at 480 ± 15 nm. SNARF-1 is a dual-emission indicator,
so fluorescence was collected simultaneously at 660 ± 40 and
580 ± 40 nm by two custom-made photodetectors, once every 6 sec.
Autofluorescence was acquired from an unstained slice in the chamber
before each experiment. The SNARF-1 fluorescence ratio (R660/580) was determined after autofluorescence (AF) was
subtracted at each emission wavelength as follows:
R660/580 = (F660  F660AF)/(F580 F580AF). In addition to compensating
for instrumental factors (i.e., illumination intensity and indicator
loading), this ratiometric technique removes activity-dependent light
scattering from the brain slice.
pH calibration. Calibration of the obtained SNARF-1
fluorescence ratio was performed using the nigericin and
high-K+ method (Boyarsky et al., 1988).
Briefly, the indicator-loaded slices were exposed to 143 mM
K+ solutions of varying extracellular pH
values (6.33, 6.46, 6.72, 6.85, 6.97, 7.07, 7.15, 7.28, and 7.44),
containing the K+ and
H+ ionophore nigericin (5 µg/ml). When
internal and external K+ concentrations
are equal, then the intracellular pH is the same value as the
extracellular pH (Boyarsky et al., 1988). After equilibration (30 min
at each point), the relationship between the fluorescence ratio and pH
was fitted by the following equation, in which R was the
fluorescence ratio of 660 nm/580 nm: pH = 7.5exp(3.2e 2.8R). Although this
calibration method, which uses living tissue, closely mimics the
experimental conditions, there may be errors in the absolute pH values.
During an actual experiment, fluorescence was measured from a
population of cells including glia and neurons and conceivably also
from the damaged cells at the surface of the brain slice. In contrast,
during calibration, the nigericin and
high-K+ solution forces the pH of the
intracellular compartments of all cells to equilibrate with the bath
pH. So, the difference in pH between different cell types or even
different compartments in a single cell is not mimicked by the
calibration method used, making the absolute values for the pH
measurements estimates.
Electrophysiological stimulation and recording.
Extracellular recording electrodes were made of microfilament capillary
thin-walled glass (0.9 mm inner diameter; 1.2 mm outer diameter; A-M
Systems) that was pulled on a micropipette puller (P-87; Sutter
Instrument Company) and filled with 2 M NaCl, resulting in
impedances between 4 and 10 M . The electrodes were placed in the
dentate cell body layer ~200 µm from the optical recording site to
avoid possible interference of light reflection from the electrode
glass with optical signals. The extracellular field potentials were
amplified and displayed on a chart recorder (AstroMed). For
antidromic stimulation, a bipolar tungsten electrode was positioned in
the hilar region (600-800 µA; 0.3 msec biphasic).
Materials. SNARF-1 AM, pluronic acid, and nigericin were
from Molecular Probes (Eugene, OR). All other reagents were from Sigma
(St. Louis, MO).
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RESULTS |
pHi was measured quantitatively in
the dentate gyrus of hippocampal slices using the pH indicator SNARF-1.
The values of resting pHi in normal ACSF ranged
from 6.93 to 7.18 (n = 10). Switching the perfusion
solution to 0 added Ca2+ and 8 mM K+ induced an
intracellular acidification of <0.03 pH units that lasted for 5-10
min. After this initial acidification, the pHi recovered to the resting values over the next 20 min (n = 5). Prolonged perfusion (>1 hr) with 0 added
Ca2+ and 8 mM
K+ medium caused periodic spontaneous
field bursts in 90% of the hippocampal slices tested. During the
spontaneous activity, the pHi showed a biphasic
response (Fig. 1). Each field burst was associated with intracellular acidification, reaching the lowest value
at the end of each field burst. After termination of the field burst,
the pHi slowly recovered. The average magnitude
of the change in pHi during the field bursts was
0.025 ± 0.003 pH units (n = 18 slices). The
measured change in pH represents the average from a population of
cells, including nonbursting cells (e.g., glia and damaged cells),
which may dilute, or reduce, the magnitude of the measured pH shift.
Therefore, the magnitude of the actual intracellular pH changes within
the bursting neurons is most likely larger than that recorded in these
experiments. In support of this possibility, we recorded larger pH
changes (up to 0.05 pH units) in some slices when the illuminated
recording area in the cell body layer was smaller than average.
However, smaller recording areas had higher noise levels, needed a
higher intensity for excitation, and had a faster bleaching of the
fluorescence, making the useful recording time shorter.
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Figure 1.
pHi changes correlate with spontaneous
field bursts in the dentate gyrus. Simultaneous field potentials
(f.p.; top trace)
and SNARF-1 fluorescence emission recordings from the dentate gyrus of
a hippocampal slice (bottom
recordings) are illustrated. The spontaneous
field bursts appeared in a regular pattern. Fluorescence intensities
(100×) were acquired at 660 ± 40 nm ( ) and 580 ± 40 nm
( ). Autofluorescence was acquired from an unstained control slice,
and corresponding ratios with autofluorescence subtracted are shown
(R660/580;  ). Titration curves of the ratio versus pH
were calculated and used to convert the fluorescence ratios to pH
( ).
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In most slices (80%) that developed spontaneous field bursts, the
burst duration and the interval between bursts were stable throughout
the experiment (~2 hr). The periodicity of these field bursts
correlated with the observed pHi changes. When
pHi decreased to a certain value, the field
bursts stopped. The recovery to a certain value coincided with the
initiation of the next field burst. In some slices (20%), however, an
occasional spontaneous field burst started before the
pHi had returned to the expected level. In these
instances the duration of that particular "early" field
burst was shorter than that of the regular recurring spontaneous bursts
(Fig. 2). This suggests that reaching a
particular level of intracellular acidification is correlated with the
termination of the field burst.
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Figure 2.
The duration of the spontaneous field bursts
correlates with acidification of the pHi. In some brain
slices (20%), an occasional spontaneous field burst started before the
pHi had recovered. Two representative examples are shown
(marked by *). In these cases the duration of the field burst
was always shorter.
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To test this observation in a more controlled manner, we initiated
field bursts with antidromic stimulation. After recording several
consecutive spontaneous field bursts, one single antidromic stimulus
was applied. When this stimulation was administered within 20 sec after
a spontaneous field burst, only a short burst of population spikes
followed the stimulation. However, when the stimulation was applied in
the middle of the interval between field bursts, it evoked a field
burst. These evoked field bursts were of shorter duration than the
regularly occurring field bursts. When the stimulus was applied later,
near the end of the interval between field bursts, it elicited a longer
duration burst. When stimulation was applied just before the predicted
spontaneous onset of field bursts, it evoked a field burst with a
duration as long as that of the spontaneous bursts (Fig.
3; n = 6). The initial
population spike evoked by antidromic stimulation at any time showed
the same amplitude as the one during the spontaneous field bursts (Fig.
3B). Simultaneous measurement of pHi
revealed that the duration of the stimulation-induced field bursts
correlated with pHi changes (Fig.
4). The pHi was
lowest just after the termination of a field burst, and stimulation at
this point only evoked multiple spikes but no field bursts (data not
shown). When the pHi had recovered to ~50% of
the total expected change, antidromic stimulation evoked a field burst
that terminated when pHi had again reached its
lowest value in that slice. The more the pHi had
recovered, the longer was the duration of the antidromically evoked
field burst (n = 3 slices).
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Figure 3.
Field bursts initiated by antidromic stimulation
vary in duration. A, After recording several consecutive
spontaneous field bursts, one single antidromic stimulation was
applied. Shortly after (<20 sec) a spontaneous field burst, antidromic
stimulation elicited only a brief burst of population spikes (1, 2).
When stimulation was applied in the middle of the interval between
field bursts, it evoked a field burst (3). The later the application of
the stimulation, the longer the duration of the evoked field burst (3, 4). B, Expanded views of the population spikes
(marked with 1-4) evoked by antidromic stimulation are shown.
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Figure 4.
Correlation of pHi with the duration
of field bursts initiated by antidromic stimulation. A,
Spontaneous field bursts (top) and the associated
pHi changes (bottom) are shown.
B, C, Antidromic stimulation (*) before
pHi had recovered to the expected level could evoke field
bursts that terminated when pHi had again reached its
lowest value in that slice.
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To test the relationship between burst duration and
pHi, we altered the burst duration by changing
the bath temperature. Measurements were taken after the temperature had
stabilized for 20 min at each point. Decreasing the bath temperature
below 30°C increased the duration of field bursts (Fig.
5A; n = 5).
Increasing the bath temperature above 30°C shortened the duration of
the field bursts. For example, the duration of the field burst induced
at 35°C was half of that induced at 25°C. Also associated with the temperature changes were changes in spiking frequency within the field
burst. Within all field bursts, the population spike frequency was
highest at the beginning of the field burst and gradually decreased
toward its termination. At higher temperatures, the spiking frequency
was faster throughout the field burst. The rate of intracellular
acidification also varied with bath temperature (Fig. 5B;
n = 3). At higher temperatures the
pHi acidified faster than at lower
temperatures.
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Figure 5.
Temperature-dependent changes in burst duration,
spike frequency, and acidification rate. A, Decreases in
the bath temperature increased the burst duration (left)
and slowed the spike frequency (middle,
right). B, Lowering the bath temperature
also slowed the acidification rate (bottom) during field
bursts (top).
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To study the interaction between the pHi and the
field burst duration further, we altered the pHi
and measured subsequent changes in the field burst duration.
Intracellular acidification with a bath perfusion of 10 or 20 mM sodium propionate blocked spontaneous field bursts
within minutes (Fig.
6A; n = 10). The spontaneous field bursts and pHi
recovered after washout of the sodium propionate. Another agent that is
widely used to modulate intracellular pH is ammonium chloride.
NH4Cl is known to induce a transient
intracellular alkalinization and a transient intracellular acidification on washout (Perez-Velazquez et al., 1994; de Curtis et
al., 1998). The duration of the field bursts increased immediately after 3 mM NH4Cl was added.
Washout of NH4Cl, producing transient intracellular acidification, blocked the field bursts (Fig.
6B; n = 5). The pH of the
extracellular medium was not changed by addition of the sodium
propionate or ammonium chloride (pH 7.38; n = 15).
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Figure 6.
Manipulation of pHi alters the
duration of the field bursts. A, Top,
Perfusion with the weak acid sodium propionate (20 mM)
blocked field bursts, which recovered after washout.
Bottom, Blockade of field bursts by sodium propionate
was associated with intracellular acidification. The pHi
returned to previous levels after washout. B,
Top, Perfusion with the weak base NH4Cl (3 mM) increased the duration of field bursts immediately
(marked by *) after NH4Cl was added to the perfusion.
Bottom, Washout of NH4Cl blocked field
bursts quickly (marked by *). Spontaneous field bursts recovered after
prolonged washout.
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Another simple way to change pHi is to change the
pH of the extracellular medium. Decreasing external pH will acidify the intracellular space (Roos and Boron, 1981). To change
pHi locally, we applied acidic medium locally (0 Ca2+ and 8 mM
K+ medium, pH 6.0) to the cell body layer
of the dentate gyrus using a blunt delivery pipette. The epileptiform
activity recorded from three electrodes placed at an interval of 300 µm along the dorsal aspect of the dentate gyrus (Fig.
7A) was highly synchronized. Although the onset of field bursts showed a delay (<1 sec), the termination of field bursts at the three sites was well synchronized. Local application of acidic medium to the middle site (site 2) blocked
the seizure activity at that location and desynchronized the other two
sites. Removal of the delivery pipette allowed recovery of the bursts
at the site of application and resynchronization of the dentate gyrus
(Fig. 7B; n = 5). If the acidic medium was applied after the initiation of a field burst, it terminated that burst
within seconds (Fig. 7C; n = 3). If the
acidic medium was applied before the initiation, it delayed the
initiation of the field burst, and the subsequent field burst was very
short (Fig. 7D; n = 5). Local application of
control medium (pH 7.38) had no effect on the duration and
synchronization of field bursts (n = 3).
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Figure 7.
The duration of the field bursts in the dentate
gyrus is altered by local pH acidification. A, Three
extracellular electrodes (1-3) were placed 300 µm apart along the
dorsal aspect of the dentate gyrus. B,
Top, Spontaneous field bursts were highly synchronized
in the whole dentate gyrus. Inset, A faster timescale
shows that the onset of field bursts at the three recording sites had a
small delay but that the termination of bursts at these sites was
completely synchronized. Middle, This set of chart
recordings shows that local application of acidic medium near the
middle electrode blocked the field burst at that location and disrupted
the synchronization between sites 1 and 3. Bottom, The
effect of local acidic medium was reversible. C, When
acidic medium was locally applied after the onset of one field burst
(*), it blocked that field burst quickly. D, If the
acidic medium was applied before the onset of one field burst (*), it
delayed the onset and stopped it early.
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DISCUSSION |
For the first time, to our knowledge, dynamic activity-dependent
pHi changes have been recorded during
epileptiform activity. Field bursts of the granule cells in the dentate
gyrus were associated with intracellular acidification. After the
termination of the field burst, the intracellular pH slowly recovered.
The data also show a direct relationship between the level of
intracellular acidification and the duration of the field bursts. It
appears that acidification to a certain threshold results in
termination of epileptiform discharges. Because many cellular processes
are pH-sensitive, intracellular acidification may be an important restraining force to prevent neuronal activity from reaching levels that threaten the integrity of normal brain function (Ransom, 1992). In
addition, these data suggest that modulation of pH homeostasis or
pH-sensitive targets may provide new therapeutic opportunities for
clinically intractable seizures.
Previous studies have suggested several possible mechanisms for seizure
termination. One possible mechanism is that elevated extracellular
potassium causes a depolarization blockade of spike generation in
neurons (Bragin et al., 1997). Alternatively, neuronal excitability may
be blocked by enhanced activity of the
Na+/K+ ATPase
(Konnerth et al., 1986). Our data demonstrate that neuronal excitability is not reduced at the end of the field bursts, when the
population spikes are still as large as (or larger than) that at the
beginning of the burst, and after the end of the field bursts, when
antidromic stimulation can evoke multiple large-amplitude population
spikes. There is evidence that extracellular potassium changes may be
involved in seizure initiation and spread (Yaari et al., 1986), but
termination of seizures, or determination of seizure duration, does not
appear to be directly related to extracellular potassium levels.
Another candidate mechanism for seizure termination is inactivation of
sodium channels. If termination of synchronized seizure activity was
caused by widespread sodium channel inactivation, we would predict that
stimulation just after a seizure would elicit no (or only a small)
amplitude response. We found that just after the termination of a field
burst, antidromic stimulation still evoked multiple spikes that showed
the same amplitude as the spontaneous field bursts. Finally, it has
been suggested that pacemaker failure is responsible for the
termination of ictal episodes in the
low-Mg2+ model of epilepsy in the
neocortex (Wong and Prince, 1990). Local application of an NMDA
receptor antagonist blocked rapid propagation across treated areas and
resulted in the emergence of spatially separate, independent pacemakers
(Wong and Prince, 1990). In our study, local application of acidic
medium blocked the synchronization in the dentate gyrus,
suggesting a similar emergence of separated, independent pacemakers.
In the present study, activity-dependent intracellular acidification
during seizure activity was recorded, but the molecular basis of the
acidification was not determined. Prolonged synchronous neuronal
activity may be expected to lower pHi via several
mechanisms. These include the metabolic production of
CO2 and lactate (Thomas and Meech, 1982; Siesj
et al., 1985), the net entry of acid through ligand- or voltage-gated
channels (Kaila and Voipio, 1987; Chen and Chesler, 1992), and
Ca2+-dependent processes (Meech and
Thomas, 1977; Wang et al., 1994). Although the field bursts were
induced in 0 added Ca2+ medium, the
interstitial Ca2+ concentration may not be
low enough to rule out the contribution of
Ca2+ entry to the intracellular
acidification process.
Our study suggests a novel explanation for seizure termination. Intense
neuronal discharges during seizure activity result in gradual
intracellular acidification. When pHi reaches a
certain threshold, it inactivates cellular processes that are necessary for continuous neuronal firing. Recent work also suggests that seizure
propagation in the nonsynaptic model is pH sensitive (Schweitzer et
al., 1998). Metabolic acidosis, which would lower
pHi, may account for the mechanism of action of
some antiepileptic treatments including carbonic anhydrase inhibitors
(Velisek and Veliskova, 1994) and the ketogenic diet (Lennox,
1928). Although at this stage the specific pathway by which
pHi could modulate seizure activity is not clear,
our findings provide strong evidence for the hypothesis that
pHi changes associated with neuronal activity can
serve as a feedback signal to modulate such activity.
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FOOTNOTES |
Received Sept. 15, 1999; revised Nov. 8, 1999; accepted Nov. 24, 1999.
This work was supported by National Institutes of Health Grants NS01784
to J.L.S. and NS33147 to P.S. We thank Drs. Eugene L. Roberts Jr for
advice on using SNARF-1 for intracellular pH measurements in slices,
Jing Qian for assistance with the optical recording and data analysis,
and Saurabh R. Sinha for advice on the indicator loading.
Correspondence should be addressed to Dr. Janet L. Stringer, Department
of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston,
TX 77030. E-mail: janets{at}bcm.tmc.edu.
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ABSTRACT
INTRODUCTION
