Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

Abstract

Granule cells in the dentate gyrus are only sparsely active in vivo and survive hippocampal sclerosis (HS) during temporal lobe epilepsy better than neighboring cells. This phenomenon could be related to intrinsic properties specifically adapted to counteract excitation. We studied the mechanisms underlying the excitability of human granule cells using acute hippocampal slices obtained during epilepsy surgery. Patch-clamp recordings were combined with pharmacology, immunocytochemistry, and computer simulations. The input resistance of granule cells correlated negatively with the duration of epilepsy and the degree of HS. Hyperpolarization-activated, ZD7288-sensitive cation (I(H), HCN) currents and highly Ba(2+)-sensitive, inwardly rectifying K(+) (Kir) currents (and HCN1 and Kir2.2 protein) were present somatodendritically and further enhanced in patients with severe HS versus mild HS. The properties and function of I(H) were characterized in granule cells. Although I(H) depolarized the membrane, it strongly reduced the input resistance and shifted the current-frequency function to higher input values. The shunting influence of HCN and Kir was similar and these conductances correlated. Resonance was not observed. Simulations suggest that the combined upregulation of Kir and HCN conductances attenuates excitatory synaptic input, while stabilizing the membrane potential and responsiveness. Thus, granule cells homeostatically downscale their input-output transfer function during epilepsy.

Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential

“…In contrast to the last point, many studies concluded that TLE does not change DG 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 (R in ); it occurred in samples of TLE patients with 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). A reasonable question is: why are there so many disparate results on the same cell type (Vida, 2009)?…”

“…With rare exceptions (Isokawa and Mello, 1991; Mehranfard et al, 2014b), most studies reporting unchanged GCs were those employing TLE models without HS. In TLE patients and the iKA TLE model, the R in of DG GCs correlates with the degree of HS (Stegen et al, 2009, 2012; Young et al, 2009). Although it cannot be ruled out that some of the studies missed R in differences due to methodological procedures, such as applying minimum R in as cell selection criterion, low seal resistance sharp electrodes, or by dissociating GC somata from their dendritic conductances (Mehranfard et al, 2014b), the conservative conclusion currently is: in TLE with HS, the ion channel expression of GCs is more drastically changed than in TLE without HS.…”

“…The molecular mechanism behind the reduced excitability of GCs is mainly transcriptional upregulation of K leak channels, i.e., channels that are open at resting membrane potential (V rest ) (Stegen et al, 2009, 2012; Young et al, 2009). Specifically, these are inwardly rectifying K (K ir ) channels of classic leak subtype K ir 2.1-4 and two pore domain K leak channels of subtype K 2P 1.1 and K 2P 6.1.…”

“…Human GCs lack the GABA A leak increase and instead show an HS-related enhancement of ZD7288-sensitive, hyperpolarization-activated cation conductance, most likely mediated by HCN1 channels (Stegen et al, 2012). Thus, contrary to prior reports (Stabel et al, 1992), a functional h-current (I H ) exists in rodent and human GCs (Young et al, 2009; Stegen et al, 2012) and this I H , as well as respective HCN1 subunits are enhanced in HS-related TLE (Bender et al, 2003; Stegen et al, 2012). The functional effect of I H in GCs is similar to the GABA A leak because E H is also between V rest and AP threshold, again contributing to enhanced shunting inhibition (Stegen et al, 2012) (see CA Section for more discussion on HCN channels).…”

TWIK-1 contributes to the intrinsic excitability of dentate granule cells in mouse hippocampus

“…The shunting influence of inwardly rectifying currents on the excitability of neuronal cells, particularly, dentate granule cells, was recently demonstrated [28]. The contribution of outwardly rectifying potassium channels to somatic shunting was described in detail for the K v 3 voltage-gated potassium channel in starburst amacrine cells [29].…”