Electrical prodromals of spreading depression void Grafstein’s potassium hypothesis
2005; American Physiological Society; Volume: 94; Issue: 5 Linguagem: Inglês
10.1152/jn.00709.2005
ISSN1522-1598
Autores Tópico(s)Neuroscience and Neuropharmacology Research
ResumoLETTERS TO THE EDITORElectrical prodromals of spreading depression void Grafstein’s potassium hypothesisOscar HerrerasOscar HerrerasPublished Online:01 Nov 2005https://doi.org/10.1152/jn.00709.2005MoreSectionsPDF (42 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat To the Editor:Anthony Strong recently essayed (Strong 2005) on Grafstein’s classic manuscript (Grafstein 1956) that launched the potassium hypothesis for the propagation of spreading depression (SD). Strong maintains that her conclusions are still valid today. However, our team and others have refuted it some time ago. The potassium hypothesis is no longer valid and a number of results have accumulated that question an essential role for potassium at any time on SD. Because Grafstein’s is still a very influential manuscript, an updated appraisal may be appropriate, so as not to mislead present and future workers in the field.Since Leao’s initial description (Leão 1944), a confusion too often found in the literature is to assume that the mechanism of SD movement can be grasped by looking into its main phase. However, it has long been established that SD is a complex chain of tightly bound events (Marshall 1959) with different thresholds, which may share or not share their macroscopic, cellular, and subcellular mechanisms. The advancing front and the main phase can be dissociated in several ways (see e.g., Herreras and Somjen 1993a). Also, many authors reported “patches” of depression that remained motionless in the elicitation locus (e.g., Largo et al. 1997). In Grafstein’s hypothesis, intense neuron firing, potassium elevation, and excitation of nearby neurons constitute the crucial cycle of events for SD movement and also accounted for the subsequent major neuron depolarization. Its long-standing success must be credited to the early finding of the associated interstitial potassium flood, which conditioned the interpretation of subsequent findings, and to the simplicity of these biophysical relations: an excitatory extracellular moraine fed by the neurons themselves (the same principle underlies the glutamate hypothesis; see Van Harreveld 1959). A number of results, scarcely mentioned in the literature, undermine the potassium hypothesis. We enlist here only a few: 1) tetrodotoxin blockade of neuron firing causes no change to SD, and thus neuron firing is not required (Sugaya et al. 1975). 2) Voltage clamping does not avoid SD-related membrane conductance (Czéh et al. 1993); initial excitation is thus not a requisite (see Somjen et al. 1991). 3) SDs may change into spreading convulsions moving at the same speed (Van Harreveld and Stamm 1953), which differentiates spreading and inactivating mechanisms. 4) Potassium and DC voltage signals follow a similar temporal course but opposite changes in magnitude (Herreras and Somjen 1993b). 5) Our latest most surprising finding shows that neurons undergo longitudinal gradients of depolarization, which are explained by the zonal dendritic opening of a large ion conductance, new equilibrium potentials, and axial currents (Canals et al. 2004), not potassium levels.The best refutation of Grafstein’s hypothesis comes from our lab (Herreras et al. 1994). We found in the hippocampal CA1 a synchronization of the initial firing among nearby neurons that presented as a high-frequency burst of population spikes ahead of the DC negativity. Even more striking is the presence of an earlier subthreshold pacemaker field oscillation seconds ahead of the potassium flood and negative potential. All this activity takes place millimeters away from the depolarizing front and is resistant to synaptic transmission blockade. These and other electrical peculiarities led us to propose direct neuron-to-neuron communication, possibly by gap junctions, to bring cells into synchronic operation and would also offer a transcellular pathway for SD propagation. The essential view of a reaction–diffusion process still holds, but available results, including Grafstein’s, are compatible with potassium being a mere coadjuvant on the chain reaction.REFERENCESCanals et al. 2005 Canals S, Makarova I, López-Aguado L, Largo C, Ibarz JM, and Herreras O. Longitudinal depolarization gradients along the somatodendritic axis of CA1 pyramidal cells: a novel feature of spreading depression. J Neurophysiol 94: 943–951, 2005.Link | ISI | Google ScholarCzéh et al. 1993 Czéh G, Aitken PG, and Somjen GG. Membrane currents in CA1 pyramidal cells during spreading depression (SD) and SD-like hypoxic depolarization. Brain Res 632: 195–208, 1993.Crossref | PubMed | ISI | Google ScholarGrafstein 1956 Grafstein B. Mechanism of spreading cortical depression. J Neurophysiol 19: 154–171, 1956.Link | ISI | Google ScholarHerreras et al. 1994 Herreras O, Largo C, Ibarz JM, Somjen GG, and Martín del Río R. Role of neuronal synchronizing mechanisms in the propagation of spreading depression in the in vivo hippocampus. J Neurosci 14: 7087–7098, 1994.Crossref | PubMed | ISI | Google ScholarHerreras and Somjen 1993a Herreras O and Somjen GG. Propagation of spreading depression among dendrites and somata of the same cell population. Brain Res 610: 276–282, 1993a.Crossref | PubMed | ISI | Google ScholarHerreras and Somjen 1993b Herreras O and Somjen GG. Analysis of potentials shifts associated with recurrent spreading depression and prolonged unstable SD induced by microdialysis of elevated K+ in hippocampus of anesthetized rats. Brain Res 610: 283–294, 1993b.Crossref | PubMed | ISI | Google ScholarLargo et al. 1997 Largo C, Tombaugh G, Aitken PG, Herreras O, and Somjen GG. Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J Neurophysiol 77: 9–16, 1997.Link | ISI | Google ScholarLeão 1944 Leão AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 7: 359–390, 1944.Link | Google ScholarMarshall 1959 Marshall WH. Spreading cortical depression of Leão. Physiol Rev 39: 239–279, 1959.Link | ISI | Google ScholarSomjen et al. 1991 Somjen GG, Segal MB, and Herreras O. Osmotic-hypertensive opening of the blood-brain barrier in rats does not necessarily provide access for potassium to cerebral interstitial fluid. Exp Physiol 76: 507–514, 1991.Crossref | PubMed | ISI | Google ScholarStrong 2005 Strong A. Dr. Bernice Grafstein’s paper on the mechanism of spreading depression. J Neurophysiol 94: 5–7, 2005.Link | ISI | Google ScholarSugaya et al. 1975 Sugaya E, Takato M, and Noda Y. Neuronal and glial activity during spreading depression in cerebral cortex of cat. J Neurophysiol 38: 822–841, 1975.Link | ISI | Google ScholarVan Harreveld 1959 Van Harreveld A. Compounds in brain extracts causing spreading depression of cerebral cortical activity and contraction of crustacean muscle. J Neurochem 3: 300–315, 1959.Crossref | PubMed | ISI | Google ScholarVan Harreveld and Stamm 1953 Van Harreveld A and Stamm JS. Spreading cortical convulsions and depressions. J Neurophysiol 16: 352–366, 1953.Link | ISI | Google ScholarjnJ NeurophysiolJournal of NeurophysiologyJ Neurophysiol0022-30771522-1598American Physiological SocietyREPLYGeorge Somjen, and Anthony StrongDepartments of Cell Biology and Neurobiology Duke University Medical Center Durham, North Carolina E-mail: [email protected] Departments of Cell Biology and Neurobiology Department of Clinical Neuroscience King’s College London, United Kingdom E-mail: [email protected]112005To the Editor: In a letter to the Editor Oscar Herreras criticizes the Editorial Focus Essay by Anthony Strong (2005) concerning the classic paper by Grafstein (1956), “Mechanism of spreading cortical depression.” Specifically, Herreras objects to the statement that Grafstein’s potassium theory of spreading depression (SD) is still valid today. Actually, he has a point.Of the several arguments marshaled by Herreras one stands out. If one records interstitial K+ concentration with an ion-selective microelectrode in normally perfused and oxygenated cerebral gray matter, an oncoming wave of propagating SD is usually not preceded by an increase in [K+]o. Rather, [K+]o increases nearly simultaneously and at the same relative rate as does the shift of extracellular voltage (for sources see Somjen 2001, 2004). Only when the energy supply is inadequate, or active transport of ions is blocked, or the tissue is cooled, do we see [K+]o increasing ahead of the large-amplitude, accelerating negative extracellular sustained potential (SP), and the depolarization of neurons that causes the SP shift. The absence of a prodromal increase in [K+]o seems to preclude the idea that diffusion of K+ ions in interstitial space is the agent mediating the propagation of SD.The numerous other data mentioned by Herreras are all important, but none refutes the K+ theory. For example, the fact that tetrodotoxin (TTX) does not block SD carries little weight in this respect because K+ evidently does flow out of neurons during SD in the presence of TTX by mechanisms other than action potentials. The impulse showers at the onset of SD were already described by Grafstein (see Fig. 2 in Strong 2005). Herreras emphasizes that synchronized subthreshold high-frequency oscillations and sometimes also impulse showers precede the increase in [K+]o. This does indeed suggest a propagating wave of electrical interaction among neurons, although similar synchronized activity can occur without subsequent SD. When SD does follow the synchronized activity, there has to be some additional mediating or triggering event.Still, even if we accept that normoxic SD does not propagate by means of the diffusion of K+ ions, Grafstein’s assertion linking the release of excess K+ from excited neurons to SD generation attests of inspired insight. In 1956 Grafstein could not measure K+ in tissue; she based her hypothesis on the careful analysis of other data. Then, a few years later, the massive release of K+ was confirmed by the Czech team (Krivánek and Bureš 1960; Vyskocil et al. 1972).To appreciate the role of K+, one must consider separately the mechanism of SD propagation from the mechanism of its generation. Marshall (1959) already emphasized that SD need not propagate. “Stationary spreading depression” might sound like a contradiction in terms, but this is a problem of semantics, not of principles. There can be little doubt that the redistribution of K+ is an essential component in the positive feedback chain that produces SD, even if it is not responsible for its initiation and its spread. A substantial amount of experimental data and computer simulations support this role of K+.The ignition of SD requires first a slowly inactivating inward membrane current (Kager et al. 2002). The main charge carrier of this current is Na+, with Ca2+ usually but not necessarily playing an important ancillary role. Under ordinary conditions, the inward current is carried through several simultaneously activated ion channels. Blocking any one of them can delay but not prevent SD (Müller and Somjen 1998). Some but not all the Na+ is accompanied by Cl−. Entry of Na+ without an anion would force K+ out of the cells in any event, but the ensuing depolarization and concomitant Ca2+ entry open various K+ channels, greatly favoring its exit. The accelerating tidal release of K+ causes additional depolarization, resulting in the nearly total neuron depolarization. The release of K+ is an essential factor giving SD its all-or-none characteristic.With respect to the mechanism of SD propagation, there are at least four competing hypotheses extant (for review see Somjen 2001, 2004). One of them has been suggested by Herreras (for references see his letter to the Editor). It is based on the concept of a wave of the opening of previously closed gap junctions among neurons. Computer simulations by Shapiro (2001) make his scheme plausible.Grafstein’s experiments were conducted on cat neocortex, whereas Herreras and coinvestigators work in hippocampal formation of rats. Differences in cytoarchitecture and in the distribution of ion channel types modify the process, but the essential features of the biophysical mechanism generating SD appear to be identical in the two regions and in all species.In conclusion, the outflow of K+ is an essential element in the SD process but it is not starting or spreading it. It was Grafstein (1956) who first suggested a critical role for K+. REFERENCESGrafstein 1956. Grafstein B. Mechanism of spreading cortical depression. J Neurophysiol 19: 154–171, 1956. Link | ISI | Google ScholarKager et al. 2002. Kager H, Wadman WJ, and Somjen GG. Conditions for the triggering of spreading depression studied with computer simulation. J Neurophysiol 88: 2700–2712, 2002. Link | ISI | Google ScholarKrivánek and Bure 1960. Krivánek J and Bureš J. Ion shifts during Leão's spreading cortical depression. Physiol Bohemoslov 9: 494–503, 1960. Google ScholarMarshall 1959. Marshall WH. Spreading cortical depression of Leão. Physiol Rev 39: 239–279, 1959. Link | ISI | Google ScholarMüller and Somjen 1998. Müller M and Somjen GG. Inhibition of major cationic inward currents prevents spreading depression-like hypoxic depolarization in rat hippocampal tissue slices. Brain Res 812: 1–13, 1998. Crossref | PubMed | ISI | Google ScholarShapiro 2001. Shapiro BE. Osmotic forces and gap junctions in spreading depression: a computational model. J Comput Neurosci 10: 99–120, 2001. Crossref | PubMed | ISI | Google ScholarSomjen 2001. Somjen GG. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81: 1065–1096, 2001. Link | ISI | Google ScholarSomjen 2004. Somjen GG. Ions in the Brain. Normal Function, Seizures and Stroke. New York: Oxford Univ. Press, 2004. Google ScholarStrong 2005. Strong A. Dr. Bernice Grafstein’s paper on the mechanism of spreading depression. J Neurophysiol 94: 5–7, 2005. Link | ISI | Google ScholarVyskocil et al. 1972. Vyskocil F, Kriz N, and Bureš J. Potassium-selective microelectrodes used for measuring the extracellular brain potassium during spreading depression and anoxic depolarization in rats. Brain Res 39: 255–259, 1972. 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