TY - JOUR
T1 - Antidepressant Effects of (S)-Ketamine through a Reduction of Hyperpolarization-Activated Current Ih
AU - Kim, Chung Sub
AU - Johnston, Daniel
N1 - Funding Information:
This work was supported by grants from National Institutes of Health grant NS084473 (D.J.), a Brain & Behavior Research Foundation Young Investigator award ( #26382 ; C.S.K.), and a McKnight Memory and Cognitive Disorder award. We thank Drs. R. Gray and D. Brager for help with the cell-attached patch experiments and all members of the Johnston and Brager laboratories for comments and suggestions throughout this study. We also thank Meagan E Volquardsen for evaluating behavioral results and Dr. Payne Y. Chang for the behavioral software.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/6/26
Y1 - 2020/6/26
N2 - Compelling evidence suggests that a single sub-anesthetic dose of (R,S)-ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanisms underlying the antidepressant effects of (R,S)-ketamine remain unclear. Here, we show that (S)-ketamine reduced dendritic but not somatic hyperpolarization-activated current Ih of dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendritic Ih in chronic unpredictable stress (CUS) rats. The reduction of Ih by (S)-ketamine was independent of NMDA receptors, barium-sensitive conductances, and cAMP-dependent signaling pathways in both unstressed and CUS groups. (S)-ketamine pretreatment before the onset of depression prevented CUS-induced behavioral phenotypes and neuropathological changes of dorsal CA1 neurons. Finally, in vivo infusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functional Ih, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or prevents Ih from being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.
AB - Compelling evidence suggests that a single sub-anesthetic dose of (R,S)-ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanisms underlying the antidepressant effects of (R,S)-ketamine remain unclear. Here, we show that (S)-ketamine reduced dendritic but not somatic hyperpolarization-activated current Ih of dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendritic Ih in chronic unpredictable stress (CUS) rats. The reduction of Ih by (S)-ketamine was independent of NMDA receptors, barium-sensitive conductances, and cAMP-dependent signaling pathways in both unstressed and CUS groups. (S)-ketamine pretreatment before the onset of depression prevented CUS-induced behavioral phenotypes and neuropathological changes of dorsal CA1 neurons. Finally, in vivo infusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functional Ih, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or prevents Ih from being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.
KW - Behavioral Neuroscience
KW - Cellular Neuroscience
KW - Neuroscience
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U2 - 10.1016/j.isci.2020.101239
DO - 10.1016/j.isci.2020.101239
M3 - Article
AN - SCOPUS:85086519057
SN - 2589-0042
VL - 23
JO - iScience
JF - iScience
IS - 6
M1 - 101239
ER -