A Sodium-Pump-Mediated Afterhyperpolarization in Pyramidal Neurons

Abstract

The sodium-potassium ATPase (i.e., the "sodium pump") plays a central role in maintaining ionic homeostasis in all cells. Although the sodium pump is intrinsically electrogenic and responsive to dynamic changes in intracellular sodium concentration, its role in regulating neuronal excitability remains unclear. Here we describe a physiological role for the sodium pump in regulating the excitability of mouse neocortical layer 5 and hippocampal CA1 pyramidal neurons. Trains of action potentials produced long-lasting (ϳ20 s) afterhyperpolarizations (AHPs) that were insensitive to blockade of voltage-gated calcium channels or chelation of intracellular calcium, but were blocked by tetrodotoxin, ouabain, or the removal of extracellular potassium. Correspondingly, the AHP time course was similar to the decay of activity-induced increases in intracellular sodium, whereas intracellular calcium decayed at much faster rates. To determine whether physiological patterns of activity engage the sodium pump, we replayed in vitro a place-specific burst of 15 action potentials recorded originally in vivo in a CA1 "place cell" as the animal traversed the associated place field. In both layer 5 and CA1 pyramidal neurons, this "place cell train" generated small, long-lasting AHPs capable of reducing neuronal excitability for many seconds. Placecell-train-induced AHPs were blocked by ouabain or removal of extracellular potassium, but not by intracellular calcium chelation. Finally, we found calcium contributions to the AHP to be temperature dependent: prominent at room temperature, but largely absent at 35°C. Our results demonstrate a previously unappreciated role for the sodium-potassium ATPase in regulating the excitability of neocortical and hippocampal pyramidal neurons.

IKCa Channels Are a Critical Determinant of the Slow AHP in CA1 Pyramidal Neurons

“…It is known that IKCa channels are apamin insensitive (Wulff et al, 2007), and we confirmed that 10 mM XE-991 had no effect on IKCa channels ( Figure S1A) and did not impede SR-evoked synaptic transmission (Vervaeke et al, 2006). Any contribution from the Na-K pump was minimized by recording at 32 C (Gulledge et al, 2013). To focus on excitatory synaptic potentials, we applied 50 mM picrotoxin to block GABAergic transmission.…”

“…Trains of SR synaptic input in WT mice (30 pulses, 50 Hz) were followed by a pronounced sAHP that peaked immediately following the train and lasted for several seconds ( Figure 2B). By comparison, recordings in KCa3.1 À/À mice revealed at most a small-amplitude sAHP following a SR stimulus train ( Figure 2B), presumably carried by the Na-K pump (Gulledge et al, 2013). Moreover, infusion of 1 mM TRAM-34 in the electrode rapidly reduced the sAHP in WT, but not KCa3.1 À/À , mice ( Figures 2B and 2C).…”

Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine

“…The medium AHP (mAHP) can also be activated by a single AP and is partially mediated by Ca 2ϩ -dependent and apamin-sensitive SK channels (Abel et al 2004;Lorenzon and Foehring 1993;Pineda et al 1998;Schwindt et al 1988b;Spain et al 1991). The mAHP is also influenced by voltage-gated K ϩ conductances, as well as I H (Gulledge et al 2013;Schwindt et al 1988bSchwindt et al , 1988cStorm 1989). The sAHP has Ca 2ϩ -and Na ϩ -dependent parts (Foehring et al 1989;Gulledge et al 2013;Schwindt et al 1988b), requires multiple APs to activate, and is insensitive to apamin.…”

“…The mAHP is also influenced by voltage-gated K ϩ conductances, as well as I H (Gulledge et al 2013;Schwindt et al 1988bSchwindt et al , 1988cStorm 1989). The sAHP has Ca 2ϩ -and Na ϩ -dependent parts (Foehring et al 1989;Gulledge et al 2013;Schwindt et al 1988b), requires multiple APs to activate, and is insensitive to apamin. The initial Ca 2ϩ -sensitive portion of the sAHP lasts ϳ1-2 s and is mediated by unknown channels that are negatively modulated by transmitters that activate PKA (e.g., NE through ␤-receptors; Andrade et al 2012;Foehring et al 1989).…”

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

“…Sources include the sodium-potassium pump, which produces a slow afterhyperpolarization (Gulledge et al 2013), channel mechanisms from different systems (Fleidervish et al 1996;Madison and Nicoll 1984;Brown and Adams 1980), and several general models (Benda and Herz 2003;Brette and Gerstner 2005). However, further research is necessary to determine their applicability to type I SGNs.…”