The paroxysmal depolarization shift in epilepsy research

Abstract

Several shortcomings with currently available pharmacotherapy of epilepsy necessitate the search for new drug targets. Paroxysmal depolarization shifts (PDS) represent the cellular correlates of electrographic (e.g. interictal) spikes. While the ionic basis of PDS is understood in great detail, controversy exists regarding their proposed implication in epilepsy. To address this issue and to consider potential targetability, this mini-review gives an overview of the ionic conductances contributing to PDS and reflects on the hypotheses of their potential pro-epileptic (epileptogenic) and anti-epileptic roles.

Keywords: Epileptogenesis; Hippocampal neurons; Interictal spike; L-type voltage-gated calcium channels.

Fig. 1. First identification, typical appearance and ionic basis of paroxysmal depolarization shifts.

A) Matsumoto and Ajmone Marsan (1964) performed simultaneous intracellular (ICR) and extracellular surface recordings (ESR) from cat cortex, on which epileptic foci were generated by topical application of penicillin. Both ictal and interictal manifestations were observed. The illustration shows the situation for interictal manifestations. The extracellular surface electrode (ESR) within the penicillin focus picked up electrographic spikes (an example is shown to the right of ESR electrode 2) at the same time as PDS were detected in subjacent neurons (this is exemplified for a recording with ICR₁ in panel B, left trace). Hence, it was concluded that PDS represent the (single-unit) cellular correlate of electrographic (“interictal”) spikes, which result from the synchronous occurrence of PDS in many neurons of the epileptic focus. PDS are distinctly different from normal action potentials (APs) that can be monitored in untreated cortex areas (e.g. with ICR2, see the right trace in panel B). B The exemplary traces highlight the differences between PDS and APs and show that PDS can occur in clusters (middle trace). The circled numbers refer to the schemes in C, which illustrate the ionic currents (I) that contribute to individual PDS formation (1-3), and to the slow depolarizing wave enabling PDS clusters (4).

Fig. 2. Putative epileptogenic implication of PDS.

Giant depolarizing potentials (GDP) arise due to excitatory GABA_A receptor-mediated signalling in immature neurons (1) and are believed to play a role in neurodevelopment by governing neuronal differentiation (2) (Ben-Ari et al., 1989) (upper left part of the figure). This role was suggested to involve Ca²⁺ influx via L-type voltage-gated Ca²⁺ channels (LTCC) and cAMP-responsive element binding protein-regulated gene transcription (CREB, inactive form; pCREB, phosphorylated active form), with brain-derived neurotrophic factor (BDNF) as a likely induced effector protein (Mohajerani et al., 2007). A similar signalling mechanism may be triggered by PDS, which arise due to excitation mediated by ion fluxes through AMPA-type glutamate receptors and LTCCs (the plus sign on an arrow indicates depolarization-induced channel activation), and can thus be envisaged to induce neuronal re-modelling (morphologically, as indicated in the figure, but also in terms of functional synaptic plasticity) in mature neurons (3, 4), thereby contributing to epileptogenesis (lower right part of the figure).