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Review
. 2013:2013:537265.
doi: 10.1155/2013/537265. Epub 2013 Jun 19.

Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication

Fuencisla Pilar-Cuéllar  1 , Rebeca Vidal, Alvaro Díaz, Elena Castro, Severiano dos Anjos, Jesús Pascual-Brazo, Raquel Linge, Veronica Vargas, Helena Blanco, Beatriz Martínez-Villayandre, Ángel Pazos, Elsa M Valdizán
Affiliations
Review

Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication

Fuencisla Pilar-Cuéllar et al. Neural Plast. 2013.

Abstract

It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ β -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies.

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Figures

Figure 1
Figure 1
RS67333 increases the number of ANPs (b) and neuroblasts type 1 (c) that express β-catenin, but not total number of QNPs cells (a). Photomicrographs illustrating β-catenin expression in neural progenitors (d), ANPs (e), and neuroblasts (f). The results are the Mean ± S.E.M. *P < 0.05 versus vehicle. Bar: 10 μM, modified from Pascual-Brazo et al., 2012 [8].
Figure 2
Figure 2
BDNF mRNA expression (a) and protein level (b) in the dentate gyrus of the hippocampus (DG) or total hippocampus, respectively, after 7-day treatment with the 5-HT4 partial agonist RS67333 (1.5 mg/kg/day) (modified from [8]) and 7-day coadministration of the SSRI fluoxetine (5 mg/kg/day) and the 5-HT2A antagonist ketanserin (0.1 mg/kg/day). *P < 0.05 versus vehicle. Modified from Pascual-Brazo et al., 2012 [8], and Pilar-Cuéllar et al., 2012 [83].
Figure 3
Figure 3
Antidepressant treatment increases basal cAMP in both rat and human. (a) Increase of basal cAMP levels in rat hippocampus, frontal cortex and striatum after chronic (14 days) antidepressant treatment with fluoxetine (10 mg/kg/day) and venlafaxine (40 mg/kg/day), and subchronic treatment (3 days) with the 5HT4 agonist RS67333 (1.5 mg/kg/day) and in postmortem frontal cortex samples from control, antidepressant free-depressed subjects (AD-free MD) and antidepressant-treated depressed subjects (AD-treated MD). cAMP is expressed in pmoles/mg protein. *P < 0.05; **P < 0.01 and ***P < 0.001 versus vehicle or control subjects; ●● P < 0.01 versus antidepressant-free depressed subjects. (b) Modulation of 5-HT1A receptor subtype-mediated inhibition of cAMP accumulation by antidepressant drugs. Chronic antidepressant treatment with fluoxetine (10 mg/kg/day) and venlafaxine (40 mg/kg/day) for 14 days downregulates 8-OH-DPAT inhibition of forskolin-induced cAMP accumulation. (a) Modified from Mostany et al., 2008 [10], Pascual-Brazo et al., 2012 [8], and unpublished results and (b) unpublished results.
Figure 4
Figure 4
Western blot analyses of hippocampal CREB (a) and p-CREB (b) levels and ratio p-CREB/CREB (c) after chronic antidepressant treatment (14 days) with fluoxetine (10 mg/kg/day) and venlafaxine (40 mg/kg/day). Note that p-CREB levels and ratio p-CREB/CREB are increased after fluoxetine treatment, but not total CREB, or after venlafaxine treatment in total cell lysate from hippocampus of rats. Values are means ± S.E.M. Corresponding to densitometry levels of the proteins expressed as the percentage of the same proteins in vehicle-treated animals. *P < 0.05 versus vehicle. Modified from Mostany et al., 2008 [10], and Mato et al., 2010 [100].
Figure 5
Figure 5
Implication on β-catenin subcellular distribution of the chronic (14 days) antidepressant treatment with the SNRI venlafaxine (40 mg/kg/day) (a), and 7-day treatment with the SSRI fluoxetine (5 mg/kg/day), the 5-HT2A antagonist ketanserin (0.1 mg/kg/day), and the combination of both (b). Note that chronic treatment with venlafaxine produces an increase in both membrane-associated and nuclear β-catenin, while the subchronic treatment with fluoxetine + ketanserin, only increases β-catenin in the membrane but not in the nuclear fraction. *P < 0.05 and ***P < 0.001 versus vehicle. (a) Modified from Mostany et al., 2008 [10], and (b) modified from Pilar-Cuellar et al., 2012 [83].
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