The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond

Abstract

Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed "interictal" because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer's disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca²⁺ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail.

Keywords: Alzheimer’s disease; L-type voltage-gated calcium channels; dendrites; electrophysiology; giant depolarizing potentials; hippocampal neurons; neuronal dysfunction; neuronal remodelling; seizures.

Figure 1

Observations in favor of an epileptogenic role of PDS. (A) Resemblance of PDS to giant depolarizing potentials (GDPs). The black trace depicts a typical PDS, which is synaptically triggered (1) and consists of action potentials of decreasing amplitude (2), a depolarized plateau (3) and termination by repolarization, sometimes below the resting membrane potential (after-hyperpolarization, (4) (to highlight the difference between a single action potential and a PDS, a hypothetical repolarization trajectory of the initial action potential is indicated by the grey line). This appearance is reminiscent of GPDs (an example is retraced in grey on the right side from a paper by Ben-Ari et al., 1989 [89]), which are widely believed to govern neuronal development [90]. In analogy, PDS may initiate various, potentially pathogenic neuronal changes. Neurodevelopmental (bottom right) and neuropathological morphological changes (bottom left) are indicated in schemes of a neuron below the traces. (B) Early appearance of electrographic spikes, the multi-unit correlate of PDS, in animal models of acquired epilepsy. Post-status epilepticus models are widely used in epilepsy research to investigate the mechanisms of epileptogenesis. In the pilocarpine version of this model [91], the cholinergic agonist pilocarpine is injected (together with non-brain-permeant methyl-scopolamine to avoid peripheral cholinergic side effects) into rats to evoke status epilepticus (SE). After 3 h, SE is terminated by the application of the benzodiazepine-type GABA_A receptor modulator diazepam. Continuous electroencephalographic recording (EEG) is performed to monitor the appearance of ictal discharges (2), which typically starts after days to weeks (chronic stage). The time until the first occurrence of seizures is referred to as the latent (or silent) stage. Electrographic spikes (1) were found to occur within 24 h after the insult (here SE), i.e., at the starting point of epileptogenesis (it should be noted that these electrographic spikes are commonly referred to as “interictal” in the literature, although the term “pre-epileptic” would be more appropriate to avoid confusion with pre-ictal or truly interictal spikes).

Figure 2

Illustration of a potential anti-ictal effect of PDS. (A,B) Two examples of electrophysiological experiments on primary rat hippocampal networks using the perforated patch-clamp technique, which indicate that PDS may inhibit seizure-like discharge activity (SLA) in an acute manner. SLA was induced repeatedly (i, ii, iii) by omission of Mg²⁺ from the superfusate (“low-Mg²⁺”-solution, application indicated by the grey horizontal bar) with recovery periods of 5 min between the stimulations. After the SLA displayed in (i), PDS were induced by co-application of 10 µM bicuculline + 3 µM Bay K8644. 5 min later, the solution was exchanged again for low Mg²⁺ solution to elicit SLA. Immediately following PDS, SLA was considerably reduced (ii). After another 5 min interval, during which PDS were not evoked, SLA appeared similar to the one during the initial control recording (iii). The discharge activity immediately preceding the switch to low-Mg²⁺ solution is shown on an expanded time scale above the SLA traces. Note that neurons showed synaptically evoked action potential discharge in (i) and (iii). Examples of the PDS that were evoked in (ii) are also displayed on the same time scale.