Emotional instability and behavioral transition in serotonin depleted mice

The hippocampus is critically involved in higher-thinking processes, such as learning, memory, cognition, emotion and motivation. Accordingly, bidirectional alterations of hippocampal activity are strongly associated with several neuropsychiatric disorders. For instance, both postmortem/imaging studies in depressed patients and experiments on animal models suggest that hippocampal hypoactivity is a core feature of depression. Conversely, increased neurogenesis and hippocampal hyperexcitability has recently been associated to bipolar disorder, according to studies performed both on bipolar patients and in animal models. The involvement of serotonin (5-HT) in mood regulation is well established. The levels of 5-HT, the cellular mechanism for its reuptake/degradation and the activity of serotonergic neurons are reported to be dysregulated in mood disorders. Selective Serotonin Reuptake Inhibitors (SSRIs) constitute the most frequently prescribed psycho-active drugs for the treatment of depression and of the depressive phase of bipolar disorder if co-administered with mood stabilizers. Most of the therapeutical effects of SSRIs take place in the hippocampus. Indeed, SSRI-mediated up-regulation of BDNF and TrkB as well as dentate gyrus neurogenesis, both down-regulated in patients and in animal models, are strictly required for antidepressant efficacy, indicating that 5-HT signaling plays a pivotal role in the hippocampal physiology. However, the molecular events underlying 5-HT regulation of hippocampal activity are still obscure. Here, we analyze the impact of brain 5-HT depletion on the genetic signature of the hippocampus by performing Next-Generation RNA sequencing on Tph2 -/- mice. We found that several transcription/growth factors, immediate-early genes as well as genes involved in synaptic plasticity and transmission are up-regulated in 5-HT depleted mice, suggesting hippocampal hyperactivity. In parallel, Tph2 -/- mice show reduced anxiety- and depression-like behaviors, escalated aggression and slower habituation in a novel environment, indicating hyperarousal. Conversely, Tph2 mutants showed an exaggerated susceptibility to chronic mild stress. Biochemical and electrophysiological analysis performed on Tph2 -/- mice accounts for their behavior, shedding new lights on the mechanisms by which serotonin governs hippocampal physiology and emotional behavior.