Abstracts

The release of glutamate from astrocytes activates synchronous slow inward currents (SICs) in hippocampal pyramidal neurons, which are exclusively mediated by the NMDA receptor, and represent a nonsynaptic mechanism to promote the synchronization of neuronal activity. Two recent studies suggest that SICs may generate paroxysmal depolarizations in neurons resembling those typical of interictal epileptiform activity and proposed that there could be an astrocytic basis of epilepsy (Tian et al. 2005, Nat Med 11:973-981; Kang et al. 2005 J Neurophysiol 57:4121-4130)., By using electrophysiological and confocal Ca²⁺ imaging experiments, we tested this hypothesis in hippocampal slices investigating the contribution of astrocytic glutamate to the generation of interictal- and ictal (seizure)-like epileptiform activity., We found that removal of extracellular Mg²⁺ and application of picrotoxin result in neuronal ictal and interictal-like epileptiform activity and long-lasting Ca²⁺ oscillations in astrocytes in the CA3 region; astrocytic Ca²⁺ activation correlates with an increased frequency of both SICs and synchronous Ca²⁺ elevations in hippocampal neurons. In paired recording experiments, SICs were found to generate neuronal depolarization and action potential discharges that occurred synchronously in neurons within 100 [mu]m of one another. Application of TTX, which does not affect either SICs or SIC-mediated neuronal synchronization, completely blocks both ictal- and interictal-like epileptiform activity in the slice. In contrast, the application of NMDA receptor antagonists, which completely block SICs, did not prevent the generation of ictal- and interictal-like events., Based on this clear-cut pharmacology, our data demonstrate that non-synaptic glutamate release from astrocytes is not necessary for the generation of epileptiform activity which relies mainly on neuronal TTX-sensitive activity., (Supported by NIH, Epilepsy Foundation and the Italian University and Health Ministries.)