Large conductance Ca2+-dependent K+ channels modulate spike width in dentate gyrus granule cells regulating excitability: A modeling study

Large-conductance voltage- and calcium-activated potassium channels (BK) contribute to the shaping of action potential (AP) waveforms in hippocampus dentate gyrus granule cells (DGCs). Blocking L-type Ca2+ channels (CaV3.1) broadens spikes in DGCs expressing gain-of-function BK channels (Wang et al., 2016). This spike broadening in the absence of Ca2+ would be expected to result in a decreased firing rate. Surprisingly, spike broadening by blocking CaV3.1 produces the opposite effect increasing the cells excitability. We hypothesize that it is this decrease in Ca2+ influx reducing the activation of Ca2+-dependent K+ channels that increases excitability in DGCs. We further hypothesize that BK activation underlies the anticonvulsive nature of hippocampal DGCs by increasing Ca2+ influx resulting in the recruitment of Ca2+-dependent SK channels.

A biophysical granule cell computer model was constructed including dendrites, soma, axon initial segment (AIS), and axon. Simulated membrane currents included fast sodium (NaV), fast and slow delayed rectifier potassium channels (f/sKDR), T-type Ca2+ (CaV3.2), β4-knockout gain-of-function large conductance voltage- and calcium-dependent potassium channels (BK-/-), small-conductance voltage-independent calcium-activated potassium channels (SK), and intracellular Ca2+ dynamics. Higher CaV3.1 conductance increases BK-/- and SK activation producing a narrower spike, greater fAHP amplitude, and increased inter-spike interval (ISI), an inhibitory effect. Inversely, eliminating CaV3.1 conductance, mimicking the effects of nifedipine, increases spike width, reducing fAHP amplitude, and shortening the ISI, an increase in excitability. This is unusual, as one would expect a decrease in excitability with a reduction in Ca2+ influx. Reducing BK-/- conductance density (GBK) increases spike half-width and ISI demonstrating BK-/- does not modulate DGC excitability. However, decreasing SK conductance (GSK) was shown to have no effect on AP width but significantly shortened ISI, an increase in excitability.

Simulations were performed at increasing frequencies of stimulation to examine the filtering properties contributed by the presence of SK and BK-/- channels. A linear relationship was observed between stimulus frequency and the number of spikes generated at varying GBK. This is expected as higher frequency stimulation and subsequent BK-/- activation would result in a decrease in spike width and slightly elevated firing rate. Simulated spike trains across the same range of frequencies at higher GSK exhibited periods of inactivation after bursts of APs. Lowering GSK simulating a decrease in channel activation increased the firing rate, demonstrating that SK is responsible for endowing DGCs with their anticonvulsive nature.