Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive burst activity from groups of neurons. Synchronized population spikes are key concomitants to seizure, but the phenomenon has remained a paradox because it cannot be explained by any known neuronal synaptic mechanism. Several lines of evidence suggest a key role of glutamate in the pathogenesis of depolarization events, which in turn trigger synchronized firing. The observation that astrocytes release glutamate via a regulated Ca2+ dependent mechanism prompted us to hypothesize that glutamate released by astrocytes plays a causal role in epileptogenesis. Our recent study snowed that chemoconvulsive agents including 4-AP and bicuculline triggered TTX-insensitive paroxysmal depolarization shifts in hippocampal slices which were closely correlated with astrocytic Ca2+ oscillations. Photolysis of caged Ca 2+ in astrocytes, but not in neurons, was sufficient to trigger local depolarization events. Furthermore, agents that blocked astrocytic glutamate release reduced epilepiform activity, with no effect on baseline EEC in adult rats. The next critical step is to expand the analysis to reactive astrocytes in epileptic animals. We propose here to analyze astrocytic Ca2+ signaling in epileptic mice with cranial window using 2-photon imaging concomitant with EEC recordings. We will correlate astrocytic signaling in reactive astrocytes with neuronal firing in epileptic mice. Reactive astrocytes are easily identified in live exposed cortex based upon the intensity of GFP emission in transgenic mice expressing GFP under the GFAP promoter. The hypothesis that the efficacy of antiepileptic drugs is better correlated with the potency by which they reduce astrocytic Ca 2+ signaling and glutamate release, than with their direct effects on synaptic transmission, will be tested. These experiments offer a new conceptual and operational approach to understanding the cellular basis of seizure disorders. If a dysregulation in Ca2+ signaling in reactive astrocytes indeed proves causal in epileptogenesis - as our preliminary data strongly suggest - then the implications of this new perspective to pharmacotherapy could be profound. By more specifically targeting the glial cause of neuronal excitability, we might be able to achieve more specific, less variable and less toxic treatment options for patients with epilepsy.
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