Abstract
Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the “acquired channelopathy” hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies.
Highlights
The relationship between epileptic seizures and ion channels is typically focused on the proepileptic nature of ion channel abnormalities
The present review focuses on temporal lobe epilepsy (TLE), because the majority of the available data concern this most common form of partial epilepsies, which in turn account for 60% of all adult epilepsy cases (Tellez-Zenteno and Hernandez-Ronquillo, 2012)
In contrast to the last point, many studies concluded that TLE does not change dentate gyrus granule cells (DG granule cells (GCs)) intrinsically (Mody et al, 1992a; Beck et al, 1996; Isokawa, 1996; Molnar and Nadler, 1999; Okazaki et al, 1999; Scharfman et al, 2003; Dietrich et al, 2005; Beck and Yaari, 2008). Contrary to both prior hypotheses, we found a decrease of the intrinsic excitability of GCs which was due to a reduction in input resistance (Rin); it occurred in samples of TLE patients with hippocampal sclerosis (HS) vs. mild/no HS as well as in iKA vs. control mice (Stegen et al, 2009, 2012; Young et al, 2009; Kirchheim et al, 2013)
Summary
The relationship between epileptic seizures and ion channels is typically focused on the proepileptic (meaning seizuresupporting) nature of ion channel abnormalities.
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