Spike firing attenuation of serotonin neurons in learned helplessness rats is reversed by ketamine. Issue 4 (1st December 2021)

• Record Type: Journal Article
• Authors: Hashimoto, Kouichi; Yamawaki, Yosuke; Yamaoka, Kenji; Yoshida, Takayuki; Okada, Kana; Tan, Wanqin; Yamasaki, Miwako; Matsumoto-Makidono, Yoshiko; Kubo, Reika; Nakayama, Hisako; Kataoka, Tsutomu; Kanematsu, Takashi; Watanabe, Masahiko; Okamoto, Yasumasa; Morinobu, Shigeru; Aizawa, Hidenori; Yamawaki, Shigeto
• Is Part Of: Brain communications. Volume 3:Issue 4(2021)
• Publication Date: 2021-12-01
• Subjects: Kv1 voltage-dependent K+ channel -- dorsal raphe nucleus -- dendrotoxin-I -- learned helplessness -- 5-HT neuron; 616
• DOI: 10.1093/braincomms/fcab285
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: Animals suffering from uncontrollable stress sometimes show low effort to escape stress (learned helplessness). Changes in serotonin (5-hydroxytryptamine) signalling are thought to underlie this behaviour. Although the release of 5-hydroxytryptamine is triggered by the action potential firing of dorsal raphe nuclei 5-hydroxytryptamine neurons, the electrophysiological changes induced by uncontrollable stress are largely unclear. Herein, we examined electrophysiological differences among 5-hydroxytryptamine neurons in naïve rats, learned helplessness rats and rats resistant to inescapable stress (non-learned helplessness). Five-week-old male Sprague Dawley rats were exposed to inescapable foot shocks. After an avoidance test session, rats were classified as learned helplessness or non-learned helplessness. Activity-dependent 5-hydroxytryptamine release induced by the administration of high-potassium solution was slower in free-moving learned helplessness rats. Subthreshold electrophysiological properties of 5-hydroxytryptamine neurons were identical among the three rat groups, but the depolarization-induced spike firing was significantly attenuated in learned helplessness rats. To clarify the underlying mechanisms, potassium (K + ) channels regulating the spike firing were initially examined using naïve rats. K + channels sensitive to 500 μM tetraethylammonium caused rapid repolarization of the action potential and the small conductance calcium-activated K + channels produced afterhyperpolarization. Additionally, dendrotoxin-I, a blocker of Kv1.1 (encoded by Kcna1 ), Kv1.2 (encoded by Kcna2 ) and Kv1.6 (encoded by Kcna6 ) voltage-dependent K + channels, weakly enhanced the spike firing frequency during depolarizing current injections without changes in individual spike waveforms in naïve rats. We found that dendrotoxin-I significantly enhanced the spike firing of 5-hydroxytryptamine neurons in learned helplessness rats. Consequently, the difference in spike firing among the three rat groups was abolished in the presence of dendrotoxin-I. These results suggest that the upregulation of dendrotoxin-I-sensitive Kv1 channels underlies the firing attenuation of 5-hydroxytryptamine neurons in learned helplessness rats. We also found that the antidepressant ketamine facilitated the spike firing of 5-hydroxytryptamine neurons and abolished the firing difference between learned helplessness and non-learned helplessness by suppressing dendrotoxin-I-sensitive Kv1 channels. The dendrotoxin-I-sensitive Kv1 channel may be a potential target for developing drugs to control activity of 5-hydroxytryptamine neurons. Abstract : Hashimoto et al. reported electrophysiological changes induced by learned helplessness in dorsal raphe serotonin neurons. The depolarization-induced spike firing was attenuated in rats showing learned helplessness. The firing attenuation was caused by upregulation of dendrotoxin-I-sensitive Kv1 channels. The firing attenuation was reversed by ketamine. Graphical Abstract: