5-HT7 receptors increase the excitability of hippocampal CA1 pyramidal neurons by inhibiting the A-type potassium current

Abstract

Accumulating evidence suggests a widespread role of serotonin 5-HT₇ receptors (5-HT₇Rs) in the physiology of cognitive and affective processing. However, we still lack insights into 5-HT₇R electrophysiology. Studies analyzing the 5-HT₇R-mediated changes in CA1 pyramidal neuron activity revealed that 5-HT₇R activation leads to the opening of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCNs). However, our group and others have shown that CA1 pyramidal cells increase their excitability following 5-HT₇R activation, an effect which cannot be explained by HCN channel opening. This suggests a different ionic mechanism might be responsible. To investigate this, we performed whole-cell patch clamp recordings of CA1 pyramidal cells in rat brain slices. It was found that acute 5-HT₇R activation increased membrane excitability and decreased spiking latency. Both effects were blocked by a selective 5-HT₇R antagonist. Spike latency in CA1 pyramidal cells is known to be regulated by transient outward voltage-dependent A-type potassium channels. Subsequent voltage clamp recordings revealed that acute 5-HT₇R activation inhibited A-type potassium currents. Pharmacological block of Kv4.2/4.3 potassium channel subunits prevented the 5-HT₇R agonist-induced changes in excitability and spiking latency, whereas blocking HCN channels had no influence on these effects. Taken together, the results reveal an ionic mechanism previously not known to be associated with 5-HT₇R activation. Inhibition of A-type potassium channels can fully account for increased CA1 pyramidal cell excitability after 5-HT₇R activation. These results can help explain a number of behavioral and physiological findings and will hopefully lead to a better understanding of 5-HT₇ receptor signaling in health and disease.

Keywords: 5-HT(7) receptor; Excitability; Hippocampus; Potassium current.