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

Florian Kirchheim,Stefanie Tinnes,Jakob Wolfart,Michael Stegen,Carola A Haas

doi:10.3389/fncel.2013.00248

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.

Highlights

The timing of action potential (AP) output is central to neuronal information processing in general and for hippocampus-dependent memory formation (Buzsaki, 2002)
The main result of the present study is that a DTX-sensitive delay current (ID) mediated by Kv1 channels controls the Action potential (AP) response delay of dentate gyrus granule (DG) cells
Our results suggest that the ID regulation of DG cells is such a homeostatic mechanism of intrinsic plasticity and that it occurs via regulation of Kv1.1 expression which constitutes an anti-epileptic mechanism of DG cells

Summary

Introduction

The timing of action potential (AP) output is central to neuronal information processing in general and for hippocampus-dependent memory formation (Buzsaki, 2002). Output regulation occurs at mossy fiber terminals of DG cells (Geiger and Jonas, 2000) and via synaptic feedback inhibition (Lawrence and McBain, 2003). The latter is thought to implement a temporal “winner-take-all” mechanism: activated DG cells compete in a race to AP threshold and fast responders silence slow neighbors (De Almeida et al, 2009). The race to threshold may be decided by subthreshold voltage-gated K+ (Kv) channels which can efficiently delay AP generation. DG cells express many types of Kv channels (Beck et al, 1992, 1996, 1997; Francis et al, 1997; Grosse et al, 2000; Riazanski et al, 2001; Rhodes et al, 2004; Ruschenschmidt et al, 2006) and it is not clear which channels govern the response delay of DG cells

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Conclusion