Elsevier

Neuroscience

Volume 141, Issue 2, 2006, Pages 1057-1068
Neuroscience

Systems neuroscience
A role for glutamate and glia in the fast network oscillations preceding spreading depression

https://doi.org/10.1016/j.neuroscience.2006.04.005Get rights and content

Abstract

The mechanism of the propagation of spreading depression is unclear. Classical theories proposed a self-maintained cycle fed by elevated potassium and/or glutamate in the extracellular space. Earlier we found in vivo a characteristic oscillatory field activity that is synchronous in a strip of tissue ahead of the oncoming wave of neuron depolarization and that occurs before the extracellular potassium level begins to rise [Herreras O, Largo C, Ibarz JM, Somjen GG, Marrín del Río R (1994) Role of neuronal synchronizing mechanisms in the propagation of spreading depression in the in vivo hippocampus. J Neurosci 14:7087–7098]. We investigated here the possible participation of glutamate and the role of glia in the prodromal field oscillations using extra and intracellular recordings and pharmacological manipulations in rat hippocampal slices. As earlier shown in vivo, field oscillations propagated ahead of the negative potential shift covering distances of up to 1 mm. The oscillatory prodromals were initially subthreshold but then each wave became crowned by a population spike. The frequency of the oscillatory prodromals was variable among slices (80–115 Hz), but constant in individual slices. The blockade of ionotropic glutamate receptors decreased the frequency of prodromal oscillations, retarded spreading depression propagation, and shortened the duration of depolarization. Blocking the glutamate membrane transport increased the oscillatory frequency. The selective metabolic poisoning of astrocytes led to gradual disorganization of prodromal oscillations whose frequency first increased and then decreased. Also, the amplitude of the population spikes within the burst diminished as individual cells fired fewer action potentials, although still phase-locked with population spikes. The effects of glial metabolic impairment were observed within the period when neuron electrical properties were still normal, and were blocked by glutamate receptor antagonists. These data suggest that glutamate released from glial cells and possibly also from neurons has a role in the generation of oscillations and neuron firing synchronization that precede the spreading depression-related depolarization, but additional mechanisms are required to fully explain the onset and propagation of spreading depression.

Section snippets

In vitro experiments

The experiments followed European Community regulations on animal care and handling and were approved by the Research Committee of the Ramón y Cajal Hospital of Madrid. Every effort was made to minimize the number of animals used and their suffering.

Hippocampal slices were prepared from female Sprague–Dawley rats (80–150 g) using standard techniques. Briefly, the animal was anesthetized with ether, decapitated and the brain removed to chilled artificial cerebrospinal fluid (ACSF). Parasagittal

Spatial features of field oscillations and the burst of PSs preceding SD in vitro

In control slices, SD waves elicited in the subicular side of the CA1 field traveled to the fimbrial side reaching the CA3 border, where they stopped. In the front of an SD wave approaching the electrode, several seconds before the onset of the characteristic sustained negative Vo, fast electrical activity was detected which subsided with the initiation of the negative DC swing (Fig. 1A). It consisted initially of a low-amplitude (0.1–0.15 mV) rhythmic (80–115 Hz) sine-like signal, which gave

Discussion

The present study focused on the mechanisms of the oscillatory field activity and firing synchronization that occurs before the inactivating depolarization associated with SD. The results suggest that endogenous Glu acting on ionotropic Glu receptors up-regulates the oscillation frequency and firing synchronization, and speeds SD migration. The metabolic poisoning of glia first increased the frequency of oscillations by a glutamatergic action, and then caused disorganization. Prolonged

Conclusion

Multiple cellular and subcellular mechanisms are activated for the propagation and depolarizing phases of SD. The present results are compatible with a glutamatergic action mediated by glia and/or neuron–glia interactions in the leading front of SD waves, and open the possibility of a participation of glia in the hypersynchronization of neuron firing by modulating synchronous oscillations between nearby neurons, which may be relevant for the treatment of stroke and epilepsy.

Acknowledgments

We thank Prof. G. G. Somjen for the critical reading of the manuscript, M. J. Yagüe for technical assistance, and American Journal Experts DLL for help with English edition. This work has been supported by grants 8.5/15/98 of the Comunidad Autónoma de Madrid and PB97/1448, BEFI 2002/1767, and BFU2005/8917 of the Spanish Ministries of Education, Science and Technology.

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    1

    Present address: Department of Clinical Neurophysiology, Epilepsy Unit, Hospital de la Princesa, Madrid 28006, Spain (J. Pastor); Department of Applied Mathematics, School of Optics, University Complutense of Madrid, Madrid 28040, Spain (L. López-Aguado).

    2

    These authors contributed equally to this work.

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