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.
Highlights
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
The induction of PDS can be explained by inhibition of GABAergic inhibition, commonly known as disinhibition, as penicillin at high doses acts as a GABAA receptor antagonist [4]
It is possible that both types of induction mechanisms may play a role; i.e., enhanced intrinsic conductances can lead to PDS even with normal synaptic activity, and PDS can occur in neurons with normal intrinsic conductances when outsized excitatory postsynaptic potentials (EPSPs) are formed
Summary
Regarding the question as to how PDS may arise, two ideas have emerged initially: the “synaptic theory” held that excessive stimulation of otherwise healthy neurons, e.g., because of recurrent synaptic feedback, was responsible for the abnormal depolarizations. Bicuculline-induced PDS only occurred when fast excitatory neurotransmission was active, because addition of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) abolished PDS discharges [27]. This indicates that synaptic imbalance can be a precipitating cause of PDS formation. 2019, 20, 577 endogenous factors that promote these abnormal electrical events (see Section 2.1), because in current injection-induced depolarizations in the presence of tetrodotoxin (when synaptic inputs and action potential discharge are disabled) the LTCC agonist Bay K8644 gave rise to PDS-like voltage responses (unpublished observations). Speckmann et al, 1990 [30] had demonstrated in earlier work that PDS elicited in-vivo in the rat motor cortex were abolished by intracellular application of the verapamil (an LTCC-antagonist)-derivative D890, whereas application of the LTCC potentiator Bay K8644 led to their augmentation
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