On the function of somatic and dendritic SK channels in cortical pyramidal neurons

Small-conductance Calcium-activated Potassium (SK) channels play an important role in regulating neuronal excitability. Recent evidence indicates SK channels regulate NMDA receptor activation in dendritic spines and play a role in regulating synaptic plasticity. Using confocal fluorescent Calcium imaging, we investigate the activation of SK channels in spines and dendrites of layer 5 (L5) cortical pyramidal neurons during action potentials (APs). The inhibition of SK channels with apamin results in a location-dependent increase in Calcium influx into dendrites and spines during backpropagating APs (average increase ~40%). This effect was occluded by block of R-type voltage-dependent calcium channels (VDCCs), but not by inhibition of N- or P/Q-type VDCCs, or block of calcium release from intracellular stores. These results indicate that dendritic SK channels regulate Calcium influx into dendrites and spines presumably by regulating the waveform of the backpropagating action potential. In addition, they show that SK channel activation is specifically controlled by Calcium influx through R-type VDCCs, complimenting previous work indicating that SK channels are located within 25-50 nm of their calcium source, in a Calcium nanodomain. SK channels have also long been known to contribute to the medium afterhyperpolarization (mAHP) at the soma for many neuronal types, including L5 pyramidal neurons, where they regulate action potential output gain and the propensity for burst firing. During the experiments using confocal Calcium imaging we noticed that the Calcium indicator used, Oregon Green BAPTA-1, which acts as a fast calcium buffer, blocked the SK mAHP. Subsequent experiments using low concentrations of the slow calcium buffer EGTA (1 mM) produced the same result, suggesting that somatic SK channels are not tightly co-localised with their calcium source. We estimate a coupling distance of greater than 150 nm, suggesting that calcium signaling between somatic SK channels and their calcium source occurs within a microdomain. Consistent with this idea, we show that all known subtypes of VDCCs except R-type were Calcium sources for the apamin-sensitive mAHP at the soma. Spike timing dependent plasticity (STDP) is a form of plasticity whereby the strength of connections between neurons in the brain are modulated following the pairing of postsynaptic APs with presynaptic activity within a narrow time window. The influx of calcium during EPSP-AP pairing is crucial to the induction of STDP. Given we show that dendritic SK channels can be activated by and influence calcium influx during bAPs, we investigated whether dendritic SK channel activation by bAPs can regulate STDP. We show that SK channels activated by bAPs significantly suppress EPSPs at negative timings for L5-L5 synaptic connections by dampening the activation of NMDA receptors. SK channels also suppressed EPSPs in layer 2/3 and hippocampal CA1 pyramidal neurons. Finally, we show that the induction of both LTP and LTD for L5-L5 synaptic connections is constrained by SK channel activation, presumably through their capacity to limit dendritic calcium influx during EPSP-AP pairing. In conclusion, these findings provide new insights into the function of SK channels and the multifaceted role calcium plays in neuronal function