Depression-like behavior and response to chronic stress in mice lacking brain serotonin

During their lives, virtually all living organisms have to face disturbing forces that upset their homeostasis. These forces, called stressors, trigger a stress response, an innate adaptive response whose task is restoring normal balance of the organism, essential for survival. In vertebrates the brain is central in the adaptation to stress, both in the perception of the stressors and in the organization of the stress response. However, due to a combination of genetic factors and environmental agents, not always a stress response is able to face the stressors, and a maladaptive stress response further destabilizes animal homeostasis, generating stress-related neuropsychiatric disorders such as depression and anxiety. Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that has a central role in normal brain function modulating several physiological processes including mood regulation and emotional behavior, and it has been implicated both in an adaptive and maladaptive stress response. Indeed, several polymorphisms identified in genes involved in serotonin signaling are associated with neuropsychiatric diseases such as depression and anxiety. Moreover, according to the monoamine hypothesis of depression, a reduction of serotonin signaling could be one of the major causes. Current antidepressants act on serotonergic signaling, elevating 5-HT concentration in the synaptic cleft, and showing therapeutic effects 2 to 4 weeks after administration, with a considerable number of patients resistant to the treatment. Therefore, the precise role of serotonin in the modulation of emotional behavior in health and disease needs to be further elucidated. We used a Tph2 knock-out mouse model to evaluate the consequences of brain serotonin depletion on the emotional behavior testing adult animals for behavioral despair. Tph2 mutant mice displayed reduced depression-like behaviors in the forced swim test, in the tail suspension test, as well as in the novelty food suppressed test. We then asked how exposure to Unpredictable Chronic Mild Stress (UCMS), an effective paradigm for inducing depression-like symptoms in rodents, could influence the behavior of animals lacking brain serotonin. Results showed that UCMS induces depressive-like behavior in the forced swim test in both Tph2 -/- and control littermates with a greater increase in immobility between non-stressed and stressed mutant mice than between non-stressed and stressed wt animals. Finally, we are currently treating stressed Tph2 -/- mice with ketamine, a NMDA-R antagonist with rapid and effective antidepressant action, in order to asses if 5-HT is required for its therapeutic effect.