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Effects of serotonin in the hippocampus: how SSRIs and multimodal antidepressants might regulate pyramidal cell function

  • Elena Dale (a1), Alan L. Pehrson (a1), Theepica Jeyarajah (a1), Yan Li (a1), Steven C. Leiser (a1), Gennady Smagin (a1), Christina K. Olsen (a2) and Connie Sanchez (a1)...


The hippocampus plays an important role in emotional and cognitive processing, and both of these domains are affected in patients with major depressive disorder (MDD). Extensive preclinical research and the notion that modulation of serotonin (5-HT) neurotransmission plays a key role in the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs) support the view that 5-HT is important for hippocampal function in normal and disease-like conditions. The hippocampus is densely innervated by serotonergic fibers, and the majority of 5-HT receptor subtypes are expressed there. Furthermore, hippocampal cells often co-express multiple 5-HT receptor subtypes that can have either complementary or opposing effects on cell function, adding to the complexity of 5-HT neurotransmission. Here we review the current knowledge of how 5-HT, through its various receptor subtypes, modulates hippocampal output and the activity of hippocampal pyramidal cells in rodents. In addition, we discuss the relevance of 5-HT modulation for cognitive processing in rodents and possible clinical implications of these results in patients with MDD. Finally, we review the data on how SSRIs and vortioxetine, an antidepressant with multimodal activity, affect hippocampal function, including cognitive processing, from both a preclinical and clinical perspective.

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The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.

Corresponding author

*Address for correspondence: Elena Dale, PhD, Lundbeck Research USA, 215 College Rd., Paramus, NJ 07652, USA. (Email:


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We would like to thank Dr. Bjarke Ebert (H Lundbeck A/S) and Simon Reid (Fusion Animation, London, United Kingdom) for assistance in preparing Figure 1 of the manuscript. This research was funded by Takeda Pharmaceuticals and H. Lundbeck A/S.



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