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The Journal of Neuroscience, March 5, 2008, 28(10):2383-2393; doi:10.1523/JNEUROSCI.4387-07.2008

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

Kevin G. Bath,¹ Nathalie Mandairon,^5 * Deqiang Jing,^1 * Rithwick Rajagopal,^7,8,9 Ruchi Kapoor,¹ Zhe-Yu Chen,¹⁰ Tanvir Khan,¹ Catia C. Proenca,¹ Rosemary Kraemer,² Thomas A. Cleland,⁶ Barbara L. Hempstead,⁴ Moses V. Chao,^7,8,9 and Francis S. Lee^1,3

Departments of ¹Psychiatry, ²Pathology, ³Pharmacology, and ⁴Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10065, Departments of ⁵Neurobiology and Behavior and ⁶Psychology, Cornell University, Ithaca, New York 14853, Departments of ⁷Cell Biology, ⁸Physiology and Neuroscience, and ⁹Psychiatry, The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, and ¹⁰Department of Neurobiology, School of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China

Correspondence should be addressed to either Francis S. Lee or Kevin G. Bath, Department of Psychiatry, Weill Medical College of Cornell University, LC-903a, 1300 York Avenue, New York, NY 10021. Email: fslee{at}med.cornell.edu. or Email: kgb2001{at}med.cornell.edu

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.

Key words: neurogenesis; olfaction; BDNF; TrkB; Val66Met; SVZ

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Received Sept. 25, 2007; revised Jan. 19, 2008; accepted Jan. 19, 2008.

Correspondence should be addressed to either Francis S. Lee or Kevin G. Bath, Department of Psychiatry, Weill Medical College of Cornell University, LC-903a, 1300 York Avenue, New York, NY 10021. Email: fslee{at}med.cornell.edu. or Email: kgb2001{at}med.cornell.edu

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BDNF Signaling during Olfactory Bulb Neurogenesis

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J. Neurosci. 2008 28: 5139-5140. [Full Text]  

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