Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus

Abstract

Granule neurons generated in the adult mammalian hippocampus synaptically integrate to facilitate cognitive function and antidepressant efficacy. Here, we investigated the role of BDNF in facilitating their maturation in vivo. We found that depletion of central BDNF in mice elicited an increase in hippocampal cell proliferation without affecting cell survival or fate specification. However, new mutant neurons failed to fully mature as indicated by their lack of calbindin, reduced dendritic differentiation and an accumulation of calretinin + immature neurons in the BDNF mutant dentate gyrus. Furthermore, the facilitating effects of GABA A receptor stimulation on neurogenesis were absent in the mutants, suggesting that defects might be due to alterations in GABA signaling. Transcriptional analysis of the mutant hippocampal neurogenic region revealed increases in markers for immature neurons and decreases in neuronal differentiation facilitators. These findings demonstrate that BDNF is required for the terminal differentiation of new neurons in the adult hippocampus.

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

“…Consistent with previous reports (Sairanen et al, 2005;Chan et al, 2008), the density of BrdU-positive cells in the DG of heterozygous BDNF knock-out mice (BDNF + /À ) was significantly lower than that observed in wild-type littermate controls (BDNF + / + ; Student's t-test, t(6) ¼ 5.74, po0.01; Figure 2a). Similarly, genetic ablation of one copy of the trkb gene (TrkB + /À ) resulted in a significant reduction in the density of surviving newly born granule cells in the DG (Student's ttest, t(6) ¼ 2.44, po0.05; Figure 2b) compared with wildtype littermate controls (TrkB + / + ).…”

“…In animal models of depression, two of the potential targets of increased trophic support are through augmentation of hippocampal neurogenesis (Castren, 2004;Sahay and Hen, 2007;Schmidt and Duman, 2007) and synaptic plasticity (Manji et al, 2003;Castren, 2004;Russo-Neustadt and Chen, 2005;Wang et al, 2008), both processes are impacted by altered BDNF levels (Figurov et al, 1996;Sairanen et al, 2005;Scharfman et al, 2005;Chan et al, 2008;Donovan et al, 2008;Li et al, 2008). We found that BDNF Met/Met mice had decreased basal levels of BDNF in the hippocampus, and unlike BDNF Val/Val mice, BDNF protein levels did not increase following chronic fluoxetine treatment.…”

“…Furthermore, during neurogenesis, the BDNF receptor, TrkB, is selectively expressed by postmitotic neuroblasts and neurons (Donovan et al, 2008). The loss of BDNF alters the neuronal fate of these cells and leads to decreased dendritic complexity of differentiated DG neurons (Chan et al, 2008). Using immunohistochemical labeling for the phosphorylated form of TrkB (pTrkB), we found pTrkB to be most highly expressed on immature (PSA-NCAMpositive) neuroblasts (Bath et al, 2008).…”

“…In previous reports, the genetic ablation of BDNF or TrkB in mice leads to a selective loss of surviving newly born but not proliferating cells of the DG (Bergami et al, 2008;Chan et al, 2008;Bergami et al, 2009;Gao and Chen, 2009). Furthermore, during neurogenesis, the BDNF receptor, TrkB, is selectively expressed by postmitotic neuroblasts and neurons (Donovan et al, 2008).…”

Compensatory Neurogenesis in the Injured Adult Brain

“…One potential mechanism may be a reduction in mitogenic factors such as FGF-2, BDNF and insulin-like growth factor 1 (IGF-1) in the epileptic hippocampus resulting in an unfavourable neurogenic environment . As neuronal differentiation rather than progenitor cell number and proliferation is predominantly affected in chronic TLE, the presence of an unfavourable hippocampal milieu due to reduction of mitogenic factors currently remains the most plausible mechanism (Altar, et al, 2004, Chan, et al, 2008.…”