Brain-Derived Neurotrophic Factor and Antidepressant Drugs Have Different But Coordinated Effects on Neuronal Turnover, Proliferation, and Survival in the Adult Dentate Gyrus

By Mikko Sairanen, Guilherme Lucas, P. Ernfors, M. Castrén, Eero Castrén. 2005

784 citations recorded by the source corpus.

Antidepressants increase proliferation of neuronal progenitor cells and expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. We investigated the role of BDNF signaling in antidepressant-induced neurogenesis by using transgenic mice with either reduced BDNF levels (BDNF+/-) or impaired trkB activation (trkB.T1-overexpressing mice). In both transgenic strains, chronic (21 d) imipramine treatment increased the number of bromodeoxyuridine (BrdU)-positive cells to degree similar to that seen in wild-type mice 24 h after BrdU administration, although the basal proliferation rate was increased in both transgenic strains. Three weeks after BrdU administration and the last antidepressant injection, the amount of newborn (BrdU- or TUC-4-positive) cells was significantly reduced in both BDNF+/- and trkB.T1-overexpressing mice, which suggests that normal BDNF signaling is required for the long-term survival of newborn hippocampal neurons. Moreover, the antidepressant-induced increase in the surviving BrdU-positive neurons seen in wild-type mice 3 weeks after treatment was essentially lost in mice with reduced BDNF signaling. Furthermore, we observed that chronic treatment with imipramine or fluoxetine produced a temporally similar increase in both BrdU-positive and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled neurons in the dentate gyrus, indicating that these drugs simultaneously increase both neurogenesis and neuronal elimination. These data suggest that antidepressants increase turnover of hippocampal neurons rather than neurogenesis per se and that BDNF signaling is required for the long-term survival of newborn neurons in mouse hippocampus.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience

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Citations in the corpus

Electroconvulsive seizure restores neurogenesis and hippocampus‐dependent fear memory after disruption by irradiation (2008, background): “…focus on VEGF and BDNF because expression of these factors is induced in the hippocampus by ECS (Nibuya et al., 1995; Newton et al., 2003), are progenitor cell mitogens (Pencea et al., 2001; Jin et al., 2002) and are implicated in neuronal survival (Storkebaum et al., 2004; Sairanen et al., 2005).”
Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways (2006, background): “decreased levels of BDNF suggest that BDNF is necessary for the long term survival of new neurons in the DG, as these mice had fewer BrdU labeled cells 3 weeks after the initial BrdU injection (Sairanen et al., 2005).”
Brain-derived Neurotrophic Factor Promotes Differentiation and Maturation of Adult-born Neurons Through GABAergic Transmission (2012, background): “Reports of neurogenesis in Bdnf heterozygous mice have also been inconclusive, with some groups reporting increased proliferation (Sairanen et al., 2005) and others reporting decreased proliferation (Lee et al.”
The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity (2010, background): “Importantly, there is evidence that antidepressants may particularly increase the turnover of new neurons in the hippocampus rather than their proliferation alone (Sairanen et al., 2005).”
Major depressive disorder. (2008, neutral): “in various brain regions [42,43], it is reasonable to postulate that improving BDNF function may be beneficial to the hippocampal neurons that are susceptible to stress-induced damages.”
Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment (2006, background): “A recent study has found that BDNF influences the survival of newborn neurons (Sairanen et al., 2005).”
The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior (2007, background): “, 2002) or no effect (Sairanen et al., 2005) on cell proliferation in the hippocampus.”
Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms (2008, background): “Likewise, growth factors regulate both the proliferation (VEGF; Cao et al, 2004) and survival (BDNF; Sairanen et al, 2005) of new hippocampal neurons.”
Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus (2012, background): “Our observations are in agreement with the findings that a functional BDNF/TrkB signaling pathway is critical for the survival of adult-born neurons (5–8) but to some extent appears to be dispensable for their proliferation and their fate commitment (7, 42).”