Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells

Abstract

Key pointsr Previous studies showed that different firing patterns of hippocampal dentate granule cells (DGCs) can trigger different network responses. However, the intrinsic DGC mechanisms controlling their excitability, spike patterns and synaptic integration in DGCs, remain poorly understood.r SK and Kv7/M channels play important roles controlling neuronal integration and excitability, but their specific roles vary between cell types. Both channel types are expressed in DGCs, but their roles are unclear.r We found that SK channels are the main generators of medium afterhyperpolarizations in DGCs, thus causing negative feedback regulation of spiking (spike frequency adaptation) and calcium influx.r In contrast, Kv7/M perform subthreshold and 'feed-forward' control of input resistance, postsynaptic integration, action potential threshold and excitability, thus weakening EPSP-spike coupling.r Thus, in DGCs, the SK and Kv7/M channels seem to perform complementary functions in postsynaptic integration and excitability control. This may have important consequences for dentate network physiology. AbstractThe dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium-duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (R input ) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased R input , lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP-spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1-EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate.

Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

“…However, previous studies have shown that in granule cells from epileptic tissue, the amplitude of low voltage–activated Ca 2+ currents was augmented, whereas the amplitude of I NaP was reportedly not increased . In addition, spike after‐hyperpolarizations are known to modulate firing pattern and excitability in granule cells . We found that the fAHP was reduced in the burst‐firing normotopic granule cells from epileptic animals, consistent with the type II granule cells found in epileptic tissue from patients .…”

Dorsoventral differences in Kv7/M‐current and its impact on resonance, temporal summation and excitability in rat hippocampal pyramidal cells

“…However, this may not be of much importance. (Mateos-Aparicio et al 2014) found that k M values in the range 7-11 mV had little effect on the predictions of their dentate granule cell model. The relative error on V M (as estimated by V half ) was fairly small [ Fig.…”

“…However, it was necessary to set the time constant τ(V M ) = 1 s in eqn (7) to obtain a difference in V half comparable to the observed one (ß5 mV). This may be considered implausible for the one-component model described in the Methods, given the observed kinetics of g M activation and deactivation (Mateos-Aparicio et al 2014;Battefeld et al 2014). However, Mateos-Aparicio et al (2014) concluded that for a number of published studies the following two-component model gave a better description of g M kinetics:…”

Modulation of Kv7 channels and excitability in the brain

“…Channels contributing to the generation of mAHP are Kv7 channels as well as SK2 calcium-activated potassium channels and HCN channels [80,103,105]. However, it has been reported that distinct channels are responsible for mAHP depending on membrane potentials and neuronal types [104,106]. …”