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1 Depto de Investigación, Hospital Ramón y Cajal, 28034 Madrid, Spain; and 2 Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Largo, Carlota, Geoffrey C. Tombaugh, Peter G. Aitken, Oscar Herreras, and George G. Somjen. Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J. Neurophysiol. 77: 9-16, 1997. We investigated whether heptanol and other long-chain alcohols that are known to block gap junctions interfere with the generation or the propagation of spreading depression (SD). Waves of SD were triggered by micro-injection of concentrated KCl solution in stratum (s.) radiatum of CA1 of rat hippocampal tissue slices. DC-coupled recordings of extracellular potential (Vo) were made at the injection and at a second site ~1 mm distant in st. radiatum and sometimes also in st. pyramidale. Extracellular excitatory postsynaptic potentials (fEPSPs) were evoked by stimulation of the Schaffer collateral bundle; in some experiments, antidromic population spikes were evoked by stimulation of the alveus. Bath application of 3 mM heptanol or 5 mM hexanol completely and reversibly prevented the propagation of the SD-related potential shift (
Vo) without abolishing the Vo at the injection site. Octanol (1 mM) had a similar but less reliably reversible effect. fEPSPs were depressed by ~30% by heptanol and octanol, 65% by hexanol. Antidromic population spikes were depressed by 30%. In isolated, patch-clamped CA1 pyramidal neurons, heptanol partially and reversibly depressed voltage-dependent Na currents possibly explaining the slight depression of antidromic spikes and, by acting on presynaptic action potentials, also the depression of fEPSPs. Fluoroacetate (FAc), a putative selective blocker of glial metabolism, first induced multiple spike firing in response to single afferent volleys and then severely suppressed synaptic transmission (confirming earlier reports) without depressing the antidromic population spike. FAc did not inhibit SD propagation. The effect of alkyl alcohols is compatible with the idea that the opening of normally closed neuronal gap junctions is required for SD propagation. Alternative possible explanations include interference with the lipid phase of neuron membranes. The absence of SD inhibition by FAc confirms that synaptic transmission is not necessary for the propagation of SD, and it suggests that normally functioning glial cells are not essential for SD generation or propagation.
Spreading depression (SD) is among the most striking and reproducible electrophysiological phenomena in CNS gray matter, yet five decades after its discovery (Leao 1944 Tissue preparation and drugs
Hippocampal slices were prepared from 80- to 150-g male Sprague-Dawley rats using standard techniques that have been described in detail elsewhere (Dingledine 1984 SD triggering and recording
SD was triggered by means of a glass micropipette with its tip broken back to a diameter of ~5 µm, filled with 1.2 M KCl, connected to a Picospritzer (General Valve Corporation), and inserted in st. radiatum of the slice. Pressure pulses (1 or 2 pulses, 200-1,000 ms, 60 psi) reliably evoked SD in control slices. An Ag-AgCl wire sealed in the back of the KCl injection pipette and connected to a DC-coupled amplifier permitted recording both the DC potential (Vo) and the evoked potential at the injection site. Vo was recorded at a second site ~1 mm distant with a 150 mM NaCl filled pipette. The injection/recording electrode is referred to as R1, the recording-only electrode as R2. The depth of each electrode was adjusted to obtain the maximal response evoked by orthodromic stimulation of the Schaffer collateral-commissural bundle using a monopolar tungsten electrode (constant current pulses 10-100 µA, 0.05-0.15 ms). Evoked potentials were monitored on an oscilloscope and digitized for later analysis (Aitken 1985
Dissociated cell whole cell recording
For patch-clamp experiments, pyramidal neurons were dissociated acutely from the hippocampal CA1 region of rat tissue slices according to the method of Kay and Wong (1986) Effects of alkyl alcohols in brain tissue slices
In six slices, SD propagation was completely blocked after 1-2 h of exposure to 3 mM heptanol and returned to control levels after washout of the heptanol (Fig. 1B). In one other slice, only partial blockade was observed and in another slice, SD was blocked but SD amplitude did not return to control levels during washout. In the presence of heptanol, the
Effect of heptanol on voltage-dependent whole cell currents in dissociated neurons
The depression of antidromic spikes could have been caused by partial suppression of voltage-dependent Na+ currents. To determine whether heptanol affects Na+ channels, four dissociated CA1 pyramidal neurons were exposed to 3 mM heptanol. Na+ current peak amplitude was depressed by an average of 60% within 100 s of heptanol application. This effect reversed almost completely upon washout(Fig. 3).
Effects of fluoroacetate
In six of seven slices, exposure to 5 mM fluoroacetate (FAc) for periods ranging from 3 to 6 h failed to block SD propagation (Fig. 4). The
These observations clearly show the power of long chain alkyl alcohols to prevent the propagation of SD. In the presence of hexanol or heptanol, the local Conclusions
There is much convergent evidence that gap junctions are required for SD propagation. Such junctions need not be open normally but must be capable of opening for SD to progress. Nevertheless, other explanations for the blocking effect by alkyl alcohols, for example the suppression of calcium currents, cannot be ruled out. Preserved SD propagation in the presence of the putative selective glial poison fluoroacetate on SD, taken together with other evidence in the literature, makes it unlikely that glial cells are essential for SD propagation.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
) the mechanism by which waves of SD propagate is still not understood. For some time, two theories have dominated discussions of this topic: the potassium theory of Grafstein (1956) and the glutamate theory of Van Harreveld (1959). There are, however, difficulties with both ideas. The facts that excess K+ can trigger SD and that K+ rises to very high levels during SD are well documented. If, however, the dispersion of K+ is the mechanism underlying the propagation of the SD wave, then at a point where brain tissue is about to be invaded by an advancing wave of SD, extracellular potassium concentration ([K+]o) should rise at first gradually up to a threshold level and then take off steeply. In fact, however, [K+]o remains steady up to the moment at which the advancing Vo arrives; it then rises suddenly and steeply only slightly after the burst of population spikes and after the onset of the negative shift of extracellular potential (Herreras and Somjen 1993a,b; Lehmenkühler 1990). Although it is clear that, once [K+]o starts to rise it must influence the evolution of SD, apparently some process initiates SD even before diffusing K+ arrives, and that K+ ions cannot be the sole agent of SD propagation.
; Herreras and Somjen 1993a; Tobiasz and Nicholson 1982). The absence of synaptic transmission does not, however, preclude the release of glutamate by means other than physiological transmission. If glutamate were the agent of SD propagation, then blockade of glutamate receptors should prevent it. Glutamate antagonists have indeed been found to increase the threshold of eliciting SD, slow down SD propagation, and limit the amplitude and duration of SD waves, but they do not completely abolish SD propagation at concentrations at which glutamate receptors are known to be blocked (Hernández-Cáceres et al. 1987; Herreras and Somjen 1993a; Marranes et al. 1988; Tegtmeier 1993). To completely suppress SD, the dose of glutamate antagonists must be raised to levels where the specificity of the compounds was doubtful. These observations indicate that glutamate facilitates SD but is not essential for its onset or propagation.
,b; Herreras et al. 1994; Somjen et al. 1992) proposed hypothetically that SD propagation is mediated not by the release of a substance from cells into interstitial fluid but by the intercellular transfer of a signal through the opening of interneuronal gap junctions that are normally closed. Among the observations that supported this idea was the eruption of a burst of population spikes of several millivolt amplitude ahead of an advancing Vo, with spikes synchronized over distances of 
1 mm (Herreras and Somjen 1993a,b; Herreras et al. 1994). Neuronal firing can be synchronized by ephaptic interaction of adjacent cells provided that interstitial resistance is high, as it is when cells are swollen (Traub et al. 1985). Cell swelling begins, however, at a given point at the same time as the shift of extracellular potential (Vo) (Jing et al. 1994) whereas the synchronized population spike shower usually precedes Vo (Herreras and Somjen 1993a; Herreras et al. 1994). This early synchronization of firing over relatively long distances is best explained by assuming electrotonic continuity between neurons. It has been reported that electrical coupling among CA1 neurons is normally sparse (MacVicar and Dudek 1980; MacVicar et al. 1982) but Andrew et al. (1982) demonstrated dye transfer in 70% of injected CA1 pyramidal cells (see also Church and Baimbridge 1991; Knowles et al. 1982; Taylor and Dudek 1982). We suggested that ordinarily closed gap junctions open ahead of the advancing SD wave and, (as has been suggested earlier), also during seizures (Perez-Velasquez et al. 1994; Somjen et al. 1985).
; Bure
et al. 1974) and by halothane, but not by chloralose (Saito et al. 1993). Halothane is known to block gap junctions (Mantz et al. 1993) but, besides this action, it is also a general anesthetic. Other support for a possible role of gap junctions came from a perceived similarity between the spread of calcium waves in cultures of astrocytes and that of SD in gray matter (Cornell-Bell et al. 1990; Finkbeiner 1992). Glial cells are believed to be normally more profusely joined by gap junctions than are neurons. Whether or not glia is the tissue that conveys SD is, however, a matter of controversy (Czéh et al. 1992; Hull and Van Harreveld 1964; Largo et al. 1996a; Somjen et al. 1993; Sugaya et al. 1975).
; Lee et al. 1994; Pott and Mechmann 1990), on SD propagation in hippocampal slices. To test the involvement of glia, we used the selective glial poison fluoroacetate (Clarke et al. 1970; Keyser and Pellmar 1994; Muir et al. 1986; Saito 1990; Szerb and Issekutz 1987).
reported that both octanol and halothane block SD in isolated chick retina. Our observations in mammalian brain slices agree with their findings.
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
; Somjen et al. 1986). Briefly, the ether-anesthetized animal was decapitated and the brain removed to ice-cold artificial cerebrospinal fluid (ACSF). One hippocampus was dissected free and cut into 0.40-mm-thick transverse slices on a MacIlwain type chopper. Slices were transferred immediately to cold ACSF and then divided between the two wells of a dual tissue slice chamber on a nylon mesh at the interface between warmed, humidified 95% O2-5% CO2 and oxygenated ACSF with the following composition (in mmol/l) 130 NaCl, 3.5 KCl, 1.2 CaCl2, 1.2 MgSO4, 1.25 NaH2PO4, 24 NaHCO3, and 10 glucose (pH 7.4, 34.5°C). ACSF flow rate was 1.5 ml/min. Slices were incubated for 90 min before beginning the experiment.
); slow DC shifts were monitored on a chart recorder and digitized to computer disk using the Axotape program (Axon Instruments). Interelectrode spacing (R1-R2) was measured in some experiments to permit calculation of absolute SD propagation velocity. Only those slices in which SD could be evoked repeatedly under control conditions were included in the analysis.
Vo at R2. SD was considered to have propagated from R1 to R2 if a sudden negative Vo of 
10 mV amplitude occurred at R2 shortly after the KCl injection. Immediately before SD was provoked, evoked orthodromic or antidromic potentials were recorded at R2 to permit assessment of changes in synaptic transmission and neural excitability.
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FIG. 1.
A: diagram of experimental arrangement. R1, KCl injection pipette also used to record extracellular potentials; R2, extracellular recording electrode; S, stimulation electrode. For some experiments, a 2nd stimulation electrode was positioned in alveus for antidromic stimulation. B: effects of heptanol on spreading depression (SD) propagation. R1, extracellular potential at KCl injection site; R2, extracellular potential at distant recording electrode. Asterisks mark KCl injections: *200-ms pulse, **400-ms pulse. Total elapsed time given at bottom. Calibration = 5 mV, 20 s.
40 min, followed by the experimental solution (heptanol, octanol or hexanol, with EtOH, in ACSF) for 1-2 h, followed by final wash in normal ACSF. Because FAc was in aqueous solution, it was administered immediately after the control period, and exposure lasted 3-6 h. In three experiments, slices were exposed to 10 mM FAc for 2 h followed by 3 mM heptanol (while continuing the FAc) for 1 h, followed by washout. In this last series of experiments, only antidromic evoked responses were monitored.
. Briefly, male Sprague-Dawley rats (100-125 g) were decapitated under ether anesthesia; 0.50-mm-thick hippocampal slices were prepared and small tissue pieces (~0.5 mm3) of the CA1 region were isolated and stirred gently for 90 min at room temperature in oxygenated N-2-hydroxyethylpiperazine-N
-2-ethanesulfonic acid (HEPES)-buffered saline containing (in mM) 125 NaCl, 5 KCl, 1 CaCl2, 2 MgCl2, 25 dextrose, and 10 HEPES, pH 7.0, containing trypsin (0.6 mg/ml; Sigma, St. Louis, MO). After digestion, tissue pieces were washed 3 times with trypsin-free buffer, pH 7.4, and incubated at room temperature in fresh buffer continually stirred under pure oxygen until needed. Cells were dissociated as needed by triturating two to three tissue blocks in a small volume (100-200 µl) of control recording solution (see below) with a graded series of fire-polished Pasteur pipettes (1.0-0.25 mm). The cell suspension was placed in an open perfusion chamber (volume = 200-300 µl) mounted on the stage of an inverted microscope (Nikon Diaphot). The cells were allowed to settle (~5 min), and the chamber was perfused with recording solution at a rate of 300-400 µl/min. Pyramidal or spindle-shaped cells were chosen according to the following criteria: a smooth, nongranular appearance with a branched or unbranched apical dendrite of at least two somal lengths. Sodium currents were recorded using electrodes pulled from thin-walled 1.5-mm borosilicate glass capillaries (World Precision Instruments, Sarasota, FL) on a Sutter P-80 pipette puller. The electrode filling solution contained (in mM) 100 CsF, 10 HEPES, 20 tetraethylammonium chloride (TEA-Cl), 2 MgCl2, 0.5 CaCl2, 10 ethylene glycol-bis(
-aminoethyl ether)-N,N,N,N-tetraacetic acid, and 2 Na2-ATP; pH adjusted to 7.2 with CsOH. Electrodes typically had open-tip resistances of 2-3 M
. The external solution consisted of (in mM) 10 NaCl, 95 choline-Cl, 20 CsCl, 1.8 CaCl2, 1 MgCl2, 10 HEPES, 5 TEA-Cl, and 25 dextrose, with 400 µM CdCl2 added to block calcium currents; pH adjusted to 7.4 with CsOH. Currents were recorded under whole cell voltage clamp with a Dagan PC-1 amplifier, sampled at 20 kHz, filtered at 3 kHz with a 3-pole low pass Bessel filter and stored on a PC using a TL-1 Labmaster A/D converter and "PClamp" software (version 5) from Axon Instruments. After seal rupture, capacitive artifacts were canceled electronically and series resistance was compensated 50-80%. Active currents were evoked by a series of depolarizing 10-mV voltage steps from a holding potential of 
70 mV preceded by a 200-ms hyperpolarizing prepulse to 120 mV to remove inactivation. Scaled leak currents were subtracted off-line.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
Vo at the injection site became smaller, indicating decreased depolarization of the cells upon KCl injection. To be sure that true SD was elicited at the injection site during heptanol exposure, we routinely increased the size of the KCl injection until the local Vo became comparable in amplitude with those obtained before heptanol application. With the local Vo restored, propagated SD wave was occasionally detected, but its amplitude was blunted, and propagation eventually failed even with the increased KCl injections (Fig. 1B). Thus it appears that in addition to blocking SD propagation, heptanol also raised the threshold for evoking SD locally.
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FIG. 2.
Effects of heptanol on evoked potentials. A: extracellular excitatory postsynaptic potentials (fEPSPs) recorded before (cont.), during (help.), and after (wash) application of heptanol. B: averaged input/output curves from 7 experiments. EtOH: 51.5 mM; heptanol: 3 mM.
0.5 mM, octanol had no detectable effect on SD (n = 2). In a separate series of experiments, hexanol (5 mM) also abolished SD propagation with full (3/6) or partial (3/6) recovery upon washout. Octanol and heptanol depressed the fEPSP to a similar extent (30 ± 5%, n = 6 for heptanol; 33 ± 14%, n = 3 for octanol); the depression caused by hexanol was more pronounced (65 ± 9%, n = 6). Overall, octanol was less consistent than either hexanol or heptanol in blocking SD, but the fact that all three alcohols had an effect strengthens our conclusion that gap junctions are required for SD propagation.
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FIG. 3.
Whole cell neuronal Na+ currents are reversibly suppressed by heptanol. A: representative Na+ currents evoked by depolarizing voltage steps (inset) before and during exposure to 3 mM heptanol (45 mM EtOH was present throughout each experiment). B: summary current-voltage relation for Na+ currents during heptanol exposure and after washout (n = 4). On average, currents were depressed by 60% although they never fully recovered during washout. Reversal potential of these currents (near +20 mV) closely matched that predicted from nominal internal and external Na+ concentrations (10 mM external, 4 mM internal: calculated Erev = +23mV ). C: summary of time course of current inhibition by 3 mM heptanol (n = 4).
Vo shift progressively increased in duration. Synaptic transmission was gradually suppressed over this period, as shown in Fig. 5, A and B. While the fEPSP began to decrease, there was sometimes a brief period of hyperexcitability during which multiple population spikes were observed in response to a sibgle orthodromic stimulus. This hyperexcitability was not quantified, but its occurrence is consistent with the impairment of extracellular K+ buffering that would be expected with glial poisoning. Antidromic responses were not significantly affected by FAc (not shown).
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FIG. 4.
Effects of 5 mM fluoroacetate on SD propagation. R1, extracellular potential at KCl injection site; R2, extracellular potential at distant recording electrode. Asterisks mark KCl injection times. Calibration = 10 mV, 20 s. Time of exposure to fluoroacetate given at top.
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FIG. 5.
A: fEPSPs evoked during 5 h of fluoroacetate exposure showing gradual suppression of response. B: input/output curves from 5 slices showing changes in fEPSP slope caused by 5 mM fluoroacetate (2- and 5-h exposure).
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
Vo at the site of the injection also was depressed, indicating diminished depolarization of the cells exposed to the injected KCl. The local depolarization could, however, be restored by raising the dose of injected KCl, yet SD propagation eventually failed even from this restored localized Vo (Fig. 1). It is also remarkable that, when SD did propagate under these conditions, its velocity was not slowed by heptanol, suggesting an all-or-none type conduction mechanism. That octanol had a similar if less reliably reversible effect reinforces the generality of this effect among alkyl alcohols. The concentrations of heptanol and octanol we used were higher than what is required to block gap junctions among cultured cells (e.g., Sontheimer et al. 1991) but were in the range used by others in brain tissue slices (Rörig et al. 1996; Yuste et al. 1995) and in retina (Martins-Ferreira and Ribeiro 1995; Nedergaard et al. 1995).
) and for octanol in cultured astrocytes (Sontheimer et al. 1991). The mechanism of the synaptic depression is not clear but could be related to a depression of action potentials or of calcium currents in presynaptic terminals. However, neither failure of synaptic transmission nor block of Na+ channels can explain the failure of SD propagation caused by heptanol. In the presence of FAc, synaptic transmission failed, yet SD propagation was unimpaired. As has been repeatedly shown, blockade of voltage-gated Na+ channels by tetrodotoxin (TTX) also does not inhibit SD propagation (Garcia Ramos and De la Cerda 1974; Sugaya et al. 1975; Tobiasz and Nicholson 1982).
Vo at the site of high-K+ application, or the SD-like depolarization caused by hypoxia (Jing et al. 1993). The mechanism of by which Ni2+ affects SD propagation remains to be explored. Ni2+ is known to block voltage-gated Ca2+ channels, but it may have other effects as well. Chebabo et al. (1993) reported the two local anesthetic agents, lidocaine and benzocaine arrest the circling SD in chick retina. To explain the difference between the SD block by local anesthetics and the lack thereof by TTX, Chebabo et al. (1993) point to the ability of the former to dissolve in the membrane lipid. Long-chain alkyl alcohols such as heptanol and octanol are also lipophilic. Whether or not local anesthetics interfere with gap junction function has, to our knowledge, not been explored. Earlier, Van Harreveld and Stamm (1953) reported that diethyl-ether does while pentobarbital does not block SD. Ether is another highly lipophilic compound. Whether it has an effect on gap junctions is, again, not known.
; Clarke et al. 1970; Keyser and Pellmar 1994; Muir et al. 1986; Paulsen et al. 1987; Saito 1990; Szerb and Issekutz 1987). The lack of an effect on SD by FAc confirms earlier similar finding by Largo et al. (1996a) who administered fluorocitrate by microdialysis to hippocampus of intact brain of anesthetized rats. They reported that, similarly to FAc, fluorocitrate blocked synaptic transmission but did not interfere with SD. The anesthetized rats used by Largo et al. (1996a) were older than the ones from which we prepared our tissue slices, demonstrating that the findings were not peculiar to immature brain tissue. These observations suggest that intact glial function is not required for SD initiation or propagation. Largo et al. (1996a) also confirmed that 4 h of fluorocitrate microdialysis caused early morphological changes of glial cells while neurons were affected only after 8 h. It may be argued, however, that interglial gap junctions could continue to function even if the energy metabolism of the glial cells is impaired and, presumably, their membrane potential reduced or abolished.
found that SD failed to invade a cortical glial scar. In addition, voltage-clamp experiments in this laboratory revealed that during SD neurons exhibit a very large increase of input conductance, whereas glial cells show little or no change, even though the reversal potential (zero-current potential) of the glial I-V plot shifted in the depolarizing direction, as expected from the elevated [K+]o (Czéh et al. 1992; Somjen et al. 1993).
), their density among neurons in adult nervous systems is less clear. There is increasing evidence that gap junctions play a role in the early development of gray matter, and the number of patent gap junctions appears to decrease with maturation of the brain (Kandler and Katz 1995). Both electrotonic and dye coupling among neurons, including pyramidal cells of CA1 region, however, has been reported in tissue slices as well is in intact brain of young as well as adult rats and guinea pigs (Andrew et al. 1982; Baimbridge et al. 1991; Knowles et al. 1982; MacVicar et al. 1982) and such functional connections can be modulated by pH and by [Ca2+]o (Church and Baimbridge 1991; Perez-Velasquez et al. 1994). At least one report claims increase of electrotonic coupling in senescent rats (Barnes et al. 1987). In rats of 250-300 g body weight, gap junction protein associated with pyramidal neurons and granule cells has been located in all areas of the hippocampus, although less abundantly in the CA1 region than in CA2 and CA3 (Yamamoto et al. 1989).
). We have proposed, hypothetically, that SD propagation requires the opening of electrotonic junctions among neurons that may, under quiescent conditions, be closed. The data presented here are compatible with this hypothesis.
; Herreras and Somjen 1993a,b; Marranes et al. 1988; Tegtmeier 1993). Therefore, it seems that glutamate facilitates but does not mediate SD propagation.
; Largo et al. 1996a; Saito 1990), has been attributed to the failure of poisoned glial cells to supply glutamine, the precursor of glutamate, to neurons, or to swelling of glia that could disrupt synaptic structure (Largo et al. 1996a). Besides failure of synaptic transmission, the firing of multiple population spikes in response to single orthodromic volleys suggests impaired glial function. Slowed clearing of excess [K+]o could cause such hyperexcitability. The prolongation of SD waves during FAc treatment could have a similar explanation, except that SD waves tend to increase in duration when repeatedly provoked in anesthetized intact brains in the absence of FAc or other drugs (Chebabo et al. 1995; Herreras and Somjen 1993b). We did not examine whether the prolongation of SD-related Vo shifts under the influence of FAc is significantly greater than what would be seen otherwise.
). The higher dose used in our study could raise questions about the selectivity of the compound. However, the preservation of antidromic spike conduction in the presence of FAc demonstrates that neurons were viable, with well preserved membrane potential and membrane function.
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ACKNOWLEDGEMENTS |
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We thank Dr. J. V. Nadler for the use of a "Picospritzer" instrument.
This research was supported by National Institute of Neurological Disorders and Stroke Grant NS-189670 and by Grant 93/661 of the Fondo de Investigaciones Sanitarias of Spain.
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FOOTNOTES |
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Address for reprint requests: G. G. Somjen, Box 3709, Duke University Medical Center, Durham, NC 27710.
Received 15 March 1996; accepted in final form 10 September 1996.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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S. Canals, I. Makarova, L. Lopez-Aguado, C. Largo, J. M. Ibarz, and O. Herreras Longitudinal Depolarization Gradients Along the Somatodendritic Axis of CA1 Pyramidal Cells: A Novel Feature of Spreading Depression J Neurophysiol, August 1, 2005; 94(2): 943 - 951. [Abstract] [Full Text] [PDF]
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G. G. Somjen Mechanisms of Spreading Depression and Hypoxic Spreading Depression-Like Depolarization Physiol Rev, July 1, 2001; 81(3): 1065 - 1096. [Abstract] [Full Text] [PDF]
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M. Bikson, R. S. Ghai, S. C. Baraban, and D. M. Durand < |
