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.

Although a tremendous honour, it is with great sadness that this review is dedicated to Mircea's memory. Mircea has been, not only an inspiration throughout my career, but a generous and supportive friend whose kindly, incisive criticism has been a constant reminder that what we study in vitro must eventually be understood in the context of the whole system. Quoting from the Preface to his elegant monograph ‘The evolution of work on extremely simplified preparations has reached the point where some investigators are not shy to jump from single-cell properties to global brain functions, such as arousal and sleep, paroxysmal events of the epileptic type, and even conscious thinking.’ (Steriade, 2001). Bearing in mind that the properties both of single neurons and the connections between them might vary in different brain states and in different phases of cortical rhythms, in this review I summarize studies of the local circuitry of the thalamo-recipient layers 4 and 6 focussing on results obtained with dual intracellular recordings and biocytin-labelling in adult neocortical slices.