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The Journal of Neuroscience, September 6, 2006, 26(36):9312-9322; doi:10.1523/JNEUROSCI.2836-06.2006

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Cellular/Molecular
Astrocytic Glutamate Is Not Necessary for the Generation of Epileptiform Neuronal Activity in Hippocampal Slices

Tommaso Fellin,^1,2 Marta Gomez-Gonzalo,² Sara Gobbo,² Giorgio Carmignoto,² and Philip G. Haydon¹

¹Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ²Consiglio Nazionale delle Ricerche Istituto di Neuroscienze and Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, 35121 Padova, Italy

Correspondence should be addressed to Philip G. Haydon, Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine. Philadelphia, PA 19104. Email: pghaydon{at}mail.med.upenn.edu

The release of glutamate from astrocytes activates synchronous slow inward currents (SICs) in hippocampal pyramidal neurons, which are mediated by the NMDA receptor and represent a nonsynaptic mechanism to promote the synchronization of neuronal activity. Two recent studies demonstrate that SICs generate neuronal paroxysmal depolarizations resembling those typical of interictal epileptiform activity and proposed that there could be an astrocytic basis of epilepsy (Kang et al., 2005; Tian et al., 2005). We tested this hypothesis using two in vitro models of epileptiform activity in hippocampal slices. Removal of extracellular Mg²⁺ and application of picrotoxin or perfusion with 0.5 mM Mg²⁺ and 8.5 mM K⁺-containing saline result mainly in neuronal ictal- and interictal-like epileptiform activity, respectively. Although both models trigger epileptiform activity, astrocytic Ca²⁺ oscillations were increased only after slice perfusion with 0 mM Mg²⁺ and picrotoxin. The activation of astrocytic Ca²⁺ signaling correlates with an increased frequency of SICs, and, when paired neurons were within 100 µm of one another with synchronous neuronal Ca²⁺ elevations, the generation of synchronous neuronal depolarizations and action potential discharges. TTX blocked both ictal- and interictal-like epileptiform activity without affecting SICs or SIC-mediated neuronal synchronization. In contrast, NMDA receptor antagonists, which block SICs, did not prevent the generation of either ictal- or interictal-like events. Based on this clear-cut pharmacology, our data demonstrate that nonsynaptic glutamate release from astrocytes is not necessary for the generation of epileptiform activity in vitro, although we cannot exclude the possibility that it may modulate the strength of the ictal (seizure)-like event.

Key words: glia; glutamate release; epileptiform activity; epilepsy; NMDA receptor; synchrony

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Received March 16, 2006; revised Aug. 3, 2006; accepted Aug. 3, 2006.

Correspondence should be addressed to Philip G. Haydon, Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine. Philadelphia, PA 19104. Email: pghaydon{at}mail.med.upenn.edu

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				J. Petravicz, T. A. Fiacco, and K. D. McCarthy Loss of IP3 Receptor-Dependent Ca2+ Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity J. Neurosci., May 7, 2008; 28(19): 4967 - 4973. [Abstract] [Full Text] [PDF]

				S. Ding, T. Fellin, Y. Zhu, S.-Y. Lee, Y. P. Auberson, D. F. Meaney, D. A. Coulter, G. Carmignoto, and P. G. Haydon Enhanced Astrocytic Ca2+ Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus J. Neurosci., October 3, 2007; 27(40): 10674 - 10684. [Abstract] [Full Text] [PDF]

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