Point–Counterpoint: Do Interictal Spikes Trigger Seizures or Protect against Them?

Abstract

Intracellular recordings in the 1960s revealed that interictal spikes in models of focal epilepsy, which resemble those in the EEG of epilepsy patients, are due to large, long-lasting neuronal depolarizations that evoke high-frequency action potential firing (see Fig. 1). Such single neuron electrophysiological events are referred to as paroxysmal depolarization shifts (PDSs). It is estimated that a spike, detectable by EEG scalp electrodes, reflects the synchronous discharge of PDSs by several million neurons over a time span of 30–75 milliseconds (3). Two divergent hypotheses were proposed to account for the PDSs. The “synaptic theorists” viewed the PDSs as outsized synaptic potentials resulting from excessive synchronous synaptic activation of essentially normal neurons. In contrast, the “epileptic neuron theorists” proposed that the excitability properties of the neurons exhibiting PDSs are altered such that normal synaptic drive results in the abnormal PDS response. Ultimately, proponents of the synaptic view prevailed (4); however, new developments have shaken confidence in this conclusion. It is now apparent that many idiopathic epilepsies are due to genetically determined ion channel defects. Epileptic discharges in these conditions truly may result from neurons with altered intrinsic excitability properties. Moreover, it seems that ion channels that mediate the intrinsic bursting properties of neurons can be altered in acquired epileptogenesis (5). In an unexpected twist, recent evidence suggests that PDSs may not be dependent upon circuit or intrinsic abnormalities of neurons at all, but rather are generated, at least in some cases, by the release of neuroactive substances, most notably glutamate, from astrocytes (6).