Though much work has focused to synaptic changes in the nervous system that follow injury and that underlie seizure disorders, the role of glial cells in the disorder have largely been speculative. Status epilepticus, a period of repeated often intractable seizures, is followed by a latent period of epileptogenesis during which there is a delayed death of neurons in the limbic system and cellular re-organizations that lead to the acquisition of spontaneous seizures (epilepsy). We know that astrocytes become reactive following status epilepticus but how they influence neuronal function is unknown. Our previous physiological studies demonstrated that Ca2+ elevations in astrocytes evoke the release of glutamate from these glial cells (gliotransmission) which in turn regulates neuronal excitability. Recent preliminary studies, employing in vivo two-photon Ca2+ imaging, demonstrate that astrocytes exhibit a prolonged period of enhanced Ca2+ excitability following status epilepticus. Since cell-wide glial Ca2+ oscillations evoke NMDA-receptor dependent neuronal excitation that is synchronous amongst several pyramidal neurons, we propose that astrocytes contribute to the regulation of neuronal excitability and excitotoxicity following status epilepticus. By integrating two-photon microscopy and photolysis with electrophysiology and inducible cell-specific transgenic animals we will determine the relative roles of gliotransmission in the regulation of neuronal excitability and excitotoxicity. We have three aims in our project. We will test the hyptheses that: I. Status Epilepticus evokes increased astrocytic Ca2+ oscillation frequency lasting for 1-3 days that stimulates glial glutamate release. II: Ca2+ oscillations in astrocytes evoke NMDA-mediated excitation of neurons during the period of enhanced astrocyte excitability that follows status epilepticus, and III: Ca2+-dependent gliotransmission induces neuronal death by the activation of NR2B-containing NMDA receptors. Though there has been speculation about the potential role of astrocytes in epileptogenesis and epilepsy, an absence of an understanding of the properties of these glial cells together with the virtual absence of astrocyte-specific experimental manipulations has prevented an appreciation of the role of these glia in epileptogenesis. This study will shed new light on and how astrocytes contribute to epileptogenesis and will provide new insights into the generation of epilepsy that have the potential to provide a new therapeutic target for the prevention of epileptogenesis.
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