Regulation of action potential delays via voltage-gated potassium Kv1.1 channels in dentate granule cells during hippocampal epilepsy

Abstract

Action potential (AP) responses of dentate gyrus granule (DG) cells have to be tightly regulated to maintain hippocampal function. However, which ion channels control the response delay of DG cells is not known. In some neuron types, spike latency is influenced by a dendrotoxin (DTX)-sensitive delay current (ID) mediated by unidentified combinations of voltage-gated K+ (Kv) channels of the Kv1 family Kv1.1–6. In DG cells, the ID has not been characterized and its molecular basis is unknown. The response phenotype of mature DG cells is usually considered homogenous but intrinsic plasticity likely occurs in particular in conditions of hyperexcitability, for example during temporal lobe epilepsy (TLE). In this study, we examined response delays of DG cells and underlying ion channel molecules by employing a combination of gramicidin-perforated patch-clamp recordings in acute brain slices and single-cell reverse transcriptase quantitative polymerase chain reaction (SC RT-qPCR) experiments. An in vivo mouse model of TLE consisting of intrahippocampal kainate (KA) injection was used to examine epilepsy-related plasticity. Response delays of DG cells were DTX-sensitive and strongly increased in KA-injected hippocampi; Kv1.1 mRNA was elevated 10-fold, and the response delays correlated with Kv1.1 mRNA abundance on the single cell level. Other Kv1 subunits did not show overt changes in mRNA levels. Kv1.1 immunolabeling was enhanced in KA DG cells. The biophysical properties of ID and a delay heterogeneity within the DG cell population was characterized. Using organotypic hippocampal slice cultures (OHCs), where KA incubation also induced ID upregulation, the homeostatic reversibility and neuroprotective potential for DG cells were tested. In summary, the AP timing of DG cells is effectively controlled via scaling of Kv1.1 subunit transcription. With this antiepileptic mechanism, DG cells delay their responses during hyperexcitation.

Intrinsic rescaling of granule cells restores pattern separation ability of a dentate gyrus network model during epileptic hyperexcitability

“…A,B, Spr30 DG/Leak GCs). Consistent with the respective experiments (Young et al, ; Kirchheim et al, ), the leaky GCs had a similar resting potential (−77.2 mV) as the CTRL GCs (−80.1 mV) but only about 60% of the R in (Fig. A, middle panel; leaky, gray traces, 264.3 MΩ; CTRL, black traces, 429.9 MΩ) and a right shifted current–frequency ( I–F ) curve compared to CTRL GCs (Fig.…”

“…The difference between GC phenotypes of TLE models, and among TLE patients, is likely due to dissimilar degrees of hippocampal sclerosis (Stegen et al, ; Young et al, ). We have demonstrated the leaky GC phenotype in several studies, not only for our TLE model but also for TLE patients and we hypothesized that it is an adaptive cellular mechanism in response to epileptic hyperexcitation (Stegen et al, ; Young et al, ; Kirchheim et al, ). A difference between our animal model and TLE patients is that, instead of the tonic GABA A , a cation conductance via hyperpolarization‐activated nucleotide‐gated (HCN) channels was responsible for part of the increased leak in human GCs (Stegen et al, ).…”

“…When we implemented the leaky GCs (Young et al, ), the pattern separation ability of the DG was ameliorated in almost all cases. Thus, the intrinsic plasticity of GCs is able to not only enhance cell survival during pathological hyperexcitation (Kirchheim et al, ; Meier et al, ) but also maintain DG network function.…”

Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

“…MTLE‐associated changes of the physiological properties and the network integration of granule cells (Stegen et al, ; Young et al, ; Kirchheim et al, ), in particular the role of recurrent connectivity through mossy fiber sprouting, have been intensely investigated (for review see Nadler, ). In contrast, the characteristics and network integration properties of CA2 cells in MTLE are largely unknown.…”

CMOS transimpedance amplifier for biosensor signal acquisition

“…Additionally, patch clamp is a primary tool in the study of genetic disorders which disrupt normal functioning ion channels such as cystic fibrosis, fibromyalgia, and epilepsy [12][13] [14]. system where the pipette electrode is replaced with a CMOS micro-pore electrode.…”