Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination.
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.
Bath
Kevin G
KG
Department of Psychiatry, Weill Medical College of Cornell University, New York, New York 10065, USA. kgb2001@med.cornell.edu
Mandairon
Nathalie
N
Jing
Deqiang
D
Rajagopal
Rithwick
R
Kapoor
Ruchi
R
Chen
Zhe-Yu
ZY
Khan
Tanvir
T
Proenca
Catia C
CC
Kraemer
Rosemary
R
Cleland
Thomas A
TA
Hempstead
Barbara L
BL
Chao
Moses V
MV
Lee
Francis S
FS
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004193:Discrimination Learning / Q000502:physiology*; D014644:Genetic Variation; D008297:Male; D008715:Methionine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009830:Olfactory Bulb / Q000166:cytology* / Q000254:growth & development* / Q000502:physiology; D009833:Olfactory Pathways / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics; D013234:Stem Cells / Q000502:physiology; D014633:Valine / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D008715:Methionine; D020813:Receptor, trkB; D014633:Valine