Investigating anxiety and depressive-like phenotypes in genetic mouse models of serotonin depletion

Emotional disorders such as depression, panic attacks, generalized anxiety, phobias and post-traumatic stress have been associated to decreased serotonin (5-HT) function, based on the positive effects of treatments that enhance 5-HT neurotransmission. However, it has been difficult to establish a primary role for 5-HT deficiency in these diseases, making preclinical models particularly useful. Over the last ten years a variety of genetic mouse models of 5-HT depletion have been produced, complementing previous pharmacologically-based models. Initial models hindered the differentiation of the raphe 5-HT neurons, while more recently produced models suppressed 5-HT production or incapacitated 5-HT vesicular packaging and release in normally developed raphe neurons. Here, we provide an overview of 11 genetic mouse models with lowered 5-HT transmission and summarize the available behavioural investigations concerning their anxiety and depression phenotypes. Although these studies are still ongoing, some common anxiety-related traits and behavioural phenotypes have emerged. Most studies have reported decreased innate anxiety to novelty but heightened fear responses to conditioned aversive cues. This complex phenotype is in general agreement with the proposed dual function of 5-HT in modulating different defensive behaviours. Surprisingly, the depressive-like behaviours have been less studied and, so far, did not yield a consistent phenotype in standard tests. Future studies should be conducted using more ethological relevant models to conclude on the causal role of 5-HT depletion in depression. This review also describes the differences in level and regional distribution of 5-HT depletion among the available mouse models, which could contribute to the diverse phenotypes observed. This article is part of a Special Issue entitled 'Anxiety and Depression'.