Abstracts

Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown. Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting. In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity by TTX and voltage-gated Ca²⁺ channel blockers. Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources and can be triggered by photolysis of caged Ca²⁺in astrocytes. Two-photon imaging of live exposed cortex revealed that several anti-epileptics, including phenytoin, gabapentin and valproate, reduced the ability of astrocytes to transmit Ca²⁺ signaling. Our results reveal an unanticipated role for astrocytes in propagation and amplification of seizure activity. As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders. (Supported in part by NS30007 and NS38073 (MN).)