Recent hypotheses support the idea that abnormalities in neuronal structural plasticity may underlie the etiopathogenesis of major depression [1, 2]. Accordingly, it has been shown that patients and animal models of this disorder show changes in the volume of certain cerebral regions, such as the hippocampus, the medial prefrontal cortex or the amygdala, which are related to the reorganization of neuronal structure and may affect their connectivity [3, 4]. However, these structural changes are not limited to neuronal remodeling, they may also affect the production of new neurons, specially in the adult hippocampus [5–8]. Interestingly, antidepressant treatment is able to revert or block this plasticity in experimental animals and humans [9–13]. In fact, different lines of evidence indicate that both neuronal remodeling [14–17] and adult neurogenesis [12, 18] may play an important role in the way of action of antidepressant drugs.
The regulation of the expression of cell adhesion molecules is critical for the neuronal structural remodeling induced by aversive experiences or by antidepressant treatments . Previous results from our laboratory have shown that chronic treatment with the serotonin (5HT) reuptake inhibitor fluoxetine, a commonly used antidepressant, influences the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in different regions of the CNS of young-adult animals [20, 21]. Similar results have been obtained with another antidepressant, imipramine . PSA-NCAM, due to its anti-adhesive properties, creates a steric impediment for cell adhesion and, consequently, promotes structural plasticity . In fact, the changes in PSA-NCAM expression induced by chronic fluoxetine treatment are accompanied by parallel changes in the expression of the synaptic protein synaptophysin (SYN), suggesting the occurrence of synaptic remodeling . PSA-NCAM expression is abundant during development and, although it decreases markedly during adulthood, it is still detectable in many cerebral regions, such as the medial prefrontal cortex (mPFC) [23, 24], amygdala  and hippocampus , which are known to be involved in major depression. In these regions, PSA-NCAM is expressed in immature neu-rons, such as those in the hippocampal subgranular zone (SGZ)  and the subventricular zone (SVZ) , but it is also expressed in a subpopulation of mature interneurons [29, 24], which have reduced syn-aptic input and morphological features compared with other interneurons lacking PSA-NCAM . Pre-vious work in our laboratory demonstrated that 5HT, acting via 5HT3 receptors is able to regulate PSA-NCAM expression in the mPFC of adult rats .
The effects of antidepressants on neuronal plasticity are not restricted to structural remodeling of neurons and their connections, they may also influence the generation and incorporation of new neurons in the adult CNS. Chronic antidepressant treatments increase neurogenesis in the SGZ of the dentate gyrus and the SVZ of young-adult rodents [31, 32], and this increase appears to be required at least for part of the behavioral improvement observed in the treated animals . However, other studies are in disagreement with these findings and have found that antidepressants do not produce an increase in neurogenesis in the SGZ [33, 34].
Despite all these interesting findings regarding the effects of antidepressants on neuronal plasticity, it has to be noted that most of the experiments have been performed using young-adult rodents, usually 2-3 months old. Consequently, there is controversy on whether antidepressants, and specifically 5HT reuptake inhibitors, exhibit the same efficacy within different age groups. This is particularly interesting because aging influences both neurogenesis  and PSA-NCAM expression . Studies on the effects of antidepressant treatment using older animals are still scarce: Only a few works have studied neurogenesis in the SGZ [32, 37], but not in the SVZ and, to our knowledge, none has studied other types of neuronal structural plasticity.
We have analyzed the effects of 14 days of chronic fluoxetine treatment on middle-aged (8 month old) rat brains, studying the expression of PSA-NCAM and that of different presynaptic proteins in regions known to be specially affected in patients and in animal models of major depression, as well as by antidepressant treatment, such as the mPFC, the amygdala, and the hippocampus [38–42]. We have studied the expression of SYN a general synaptic marker, glutamic acid decarboxylase 65/67 (GAD6), a marker for inhibitory synapses and the vesicular glutamate transporter 1 (VGluT1), a marker of excitatory synapses. To study the effects of fluoxetine on adult neurogenesis, we have analyzed the numbers of im-mature cells, using immunohistochemistry for doublecortin (DCX) and PSA-NCAM, and those of prolife-rating cells with Ki67 in the two neurogenic niches of the adult brain: the SGZ and the SVZ.