TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment.
Adult hippocampal neurogenesis is stimulated by chronic administration of antidepressants (ADs) and by voluntary exercise. Neural progenitor cells (NPCs) in the dentate gyrus (DG) that are capable of continuous proliferation and neuronal differentiation are the source of such structural plasticity. Here we report that mice lacking the receptor tyrosine kinase TrkB in hippocampal NPCs have impaired proliferation and neurogenesis. When exposed to chronic ADs or wheel-running, no increase in proliferation or neurogenesis is observed. Ablation of TrkB also renders these mice behaviorally insensitive to antidepressive treatment in depression- and anxiety-like paradigms. In contrast, mice lacking TrkB only in differentiated DG neurons display typical neurogenesis and respond normally to chronic ADs. Thus, our data establish an essential cell-autonomous role for TrkB in regulating hippocampal neurogenesis and behavioral sensitivity to antidepressive treatments, and support the notion that impairment of the neurogenic niche is an etiological factor for refractory responses to an antidepressive regimen.
Li
Yun
Y
Department of Developmental Biology, Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133, USA.
Luikart
Bryan W
BW
Birnbaum
Shari
S
Chen
Jian
J
Kwon
Chang-Hyuk
CH
Kernie
Steven G
SG
Bassel-Duby
Rhonda
R
Parada
Luis F
LF
D053687:Adult Stem Cells; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004965:Estrogen Antagonists / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000187:drug effects*; D020813:Receptor, trkB / Q000172:deficiency / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004965:Estrogen Antagonists; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D013629:Tamoxifen; D049452:Green Fluorescent Proteins; D020813:Receptor, trkB