Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis

Mol Psychiatry. 2010 Jan;15(1):80-92. doi: 10.1038/mp.2009.67. Epub 2009 Jul 21.

Abstract

Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors*
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Bromodeoxyuridine / metabolism
  • Cell Line
  • Depression / pathology*
  • Depression / physiopathology
  • Depression / therapy*
  • Disease Models, Animal
  • Exploratory Behavior / drug effects
  • Food Preferences / drug effects
  • Glioma / pathology
  • Humans
  • Locomotion / drug effects
  • Locomotion / physiology
  • Male
  • Maze Learning / drug effects
  • Microinjections / methods
  • Microtubule-Associated Proteins / metabolism
  • Neurogenesis / drug effects
  • Neurogenesis / physiology*
  • Neuropeptides / metabolism
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Statistics, Nonparametric
  • Sucrose / administration & dosage
  • Sweetening Agents / administration & dosage
  • Swimming / psychology
  • Transfection / methods

Substances

  • Brain-Derived Neurotrophic Factor
  • Microtubule-Associated Proteins
  • Neuropeptides
  • RNA, Small Interfering
  • Sweetening Agents
  • doublecortin protein
  • Sucrose
  • Bromodeoxyuridine