The Impact of Fluoxetine Treatment on BDNF Signaling and Cellular Plasticity in the Brain

The neurotrophin hypothesis of depression, which states that the pathophysiology of depression is caused by a lack of neurotrophic support, has gained much interest over the past years. Chronic exposure to stress, a major determinant of depression decreases neurotrophin production in the brain. These neurotrophins, like brain-derived neurotrophic factor (BDNF), are critically involved in the proliferation, survival and differentiation of new neurons in the subgranular zone of the hippocampus. Besides their role in neurogenesis, neurotrophins play a pivotal role in synaptogenesis, synaptic plasticity, dendritic arborization and long-term potentiation. As such, neurotrophins are a crucial factor regulating plasticity in the brain. The functional effects of neurotrophins are evident from their important role in memory formation, cognitive function, and resilience to stress and depression. Not only do neurotrophins like BDNF have intrinsic antidepressant properties, studies show that antidepressants, including selective serotonin reuptake inhibitors (SSRI's) such as fluoxetine, critically depend on functional BDNF signaling. The neurotrophin hypothesis of depression helps explaining why antidepressants require a few weeks of administration before they become therapeutically effective, although they acutely increase neurotransmitter levels in the brain. Antidepressants increase the expression of BDNF, and as a consequence of its neurotrophic properties, they gradually increase cellular plasticity and connectivity over time. This slow repair mechanism is needed to counteract the atrophy in limbic structures of the "depressed" brain such as the hippocampus. This chapter focusses on the role of BDNF in cellular plasticity in relation to affective disorders. Special attention is given as to how BDNF signaling and its role in plasticity is implicated in the mechanism of action of antidepressants, SSRI's in particular.