The impact of calcium-activated potassium channels on dendritic excitability in cortical layer 5 pyramidal neurons

Abstract

Layer 5 pyramidal neurons are considered that main output units of the cortex. They receive input from all cortical layers onto their large dendritic tree. Dendritic spikes play a key role in the integration of synaptic inputs in these neurons, as they can modulate the gain of distal synaptic inputs and add another computational layer to the cell. These events are associated with calcium influx and therefore may be modulated by calcium-dependent processes such as calcium-activated potassium K(Ca) channels. In this study we investigate the impact of K(Ca) channels on dendritic excitability. We found that the impact of these channels on dendritic signals depends on their subcellular location and the colocalization with their Ca2+ source. Fast activating large conductance BK channels at the cell soma were found to speed up the repolarisation of a somatic action potential (AP), while dendritic BK channels curtail Ca2+ spikes in the main apical dendrites of L5 pyramidal neurons. Small conductance SK channels on the other hand are responsible for the medium after-hyperpolarisation after an AP when located at the soma, which limits neuronal output. However, when colocalized with voltage gated Ca2+ channels (VGCCs) in the distal apical dendritic tuft, these channels enhance dendritic excitability. While the mechanism for this counter-intuitive result remains elusive, we found a broadening of isolated Ca2+ spikes in the distal apical dendritic tuft, as well as an increase in input resistance, indicating that SK channels in thin distal dendritic branches may facilitate the generation of VGCC dependent spikes in the main apical trunk. Further investigation of this result showed that R-type VGCCs are the main voltage source for the activation of SK channels in the dendrite. SK channels also show a complex interaction with NMDA spikes in basal dendrites of cortical L5 pyramidal neurons. Glutamate iontophoresis experiments showed that when activated by Ca2+ influx due to the excitation of glutamatergic synapses, SK channels reduce the amplitude of NMDA spikes but also reduce their threshold. Repeating the experiments in the presence of a non-specific VGCC blocker revealed that the reduction of spike amplitude is due to SK channels, activated by Ca2+ influx through NMDA receptors, while the reduction in threshold is due to SK channels, activated by VGCCs. Therefore the effect of SK channels on dendritic signals is determined by their Ca2+ source. Finally, to investigate the effects of SK channel activation on dendritic excitability in a more physiological environment, we performed in vivo recordings, combined with targeted application of an SK channel blocker to the somatic or the dendritic region of L5 pyramidal cells. The results indicate that somatic K channels increase somatic AP output, while dendritic SK channels promote clustering of APs, indicating an enhancement of dendritic excitability. In conclusion, we found that K(Ca) channels can modulate dendritic excitability and that SK channels in particular have a quite unexpected impact on the generation of dendritic spikes in vitro, which can cause changes in neuronal output in vivo. Show more