Variant Brain-Derived Neurotrophic Factor (Val66Met) Alters Adult Olfactory Bulb Neurogenesis and Spontaneous Olfactory Discrimination

Abstract

Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.

BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

“…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 the rostral migratory stream pTrkB expression was not detectable on GFAP-positive or NeuN-positive cells (Bath et al, 2008). These effects were identical to what we observed in the DG (Supplementary Figure 1).…”

“…In previous reports, we have shown that the BDNF Val66Met SNP does not lead to a reduction in total BDNF levels in the whole brain of BDNF Met/Met mice, cultured cortical neurons from BDNF Met/Met mice (Chen et al, 2006), or cortical tissues (Bath et al, 2008). This SNP does lead to a decrease in the trafficking of BDNF to secretory vesicles and the subsequent activity-dependent release of BDNF (Egan et al, 2003;Chen et al, 2004Chen et al, , 2005.…”

“…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 the rostral migratory stream pTrkB expression was not detectable on GFAP-positive or NeuN-positive cells (Bath et al, 2008).…”

“…BrdU labeling and immunohistochemcial detection was carried out as described in Bath et al (2008). To quantify the density of BrdU positive cells in the sub-granular & granule cell layer of the DG, a profile counting method was used (described below).…”

Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory

“…Area densities of subventricular zone (SVZ) BrdU ϩ cells were derived using a method modified from Bath et al (2008). A systematic random sample fraction of 1 ⁄4 serially cut coronal sections, covering ϳ1.54 -0.50 mm relative to bregma, was used.…”