5-HT7 receptors increase the excitability of hippocampal CA1 pyramidal neurons by inhibiting the A-type potassium current. (15th October 2020)

• Record Type: Journal Article
• Authors: Siwiec, Marcin; Kusek, Magdalena; Sowa, Joanna Ewa; Tokarski, Krzysztof; Hess, Grzegorz
• Is Part Of: Neuropharmacology. Volume 177(2020)
• Publication Date: 2020-10-15
• Subjects: 5-HT7 receptor -- Hippocampus -- Excitability -- Potassium current; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108248
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Accumulating evidence suggests a widespread role of serotonin 5-HT7 receptors (5-HT7 Rs) in the physiology of cognitive and affective processing. However, we still lack insights into 5-HT7 R electrophysiology. Studies analyzing the 5-HT7 R-mediated changes in CA1 pyramidal neuron activity revealed that 5-HT7 R 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-HT7 R 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-HT7 R activation increased membrane excitability and decreased spiking latency. Both effects were blocked by a selective 5-HT7 R 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-HT7 R activation inhibited A-type potassium currents. Pharmacological block of Kv4.2/4.3 potassium channel subunits prevented the 5-HT7 R 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-HT7 R activation. Inhibition of A-type potassium channels can fully account for increased CA1 pyramidal cell excitability after 5-HT7 R 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. Highlights: Serotonin 5-HT7 receptors increase the excitability and decrease spiking latency of CA1 pyramidal cells. These effects are due to 5-HT7 R-mediated inhibition of A-type potassium channels. Blocking Kv4.2/4.3 K + channel subunits abolishes changes in excitability and spiking latency following 5-HT7 R activation. Blocking HCN channels has no influence on 5-HT7 R-mediated increase in excitability and spiking latency.