Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy.
BACKGROUND
Brain-derived neurotrophic factor (BDNF) plays an important role in neural plasticity in the adult nervous system and has been suggested as a target gene for antidepressant treatment. The neurotrophic hypothesis of depression suggests that loss of BDNF from the hippocampus contributes to an increased vulnerability for depression, whereas upregulation of BDNF in the hippocampus is suggested to mediate antidepressant efficacy.


METHODS
We have used a viral-mediated gene transfer approach to assess the role of BDNF in subregions of the hippocampus in a broad array of behavioral paradigms, including depression-like behavior and antidepressant responses. We have combined the adeno-associated virus (AAV) with the Cre/loxP site-specific recombination system to induce the knockout of BDNF selectively in either the CA1 or dentate gyrus (DG) subregions of the hippocampus.


RESULTS
We show that the loss of BDNF in either the CA1 or the DG of the hippocampus does not alter locomotor activity, anxiety-like behavior, fear conditioning, or depression-related behaviors. However, the selective loss of BDNF in the DG but not the CA1 region attenuates the actions of desipramine and citalopram in the forced swim test.


CONCLUSIONS
These data suggest that the loss of hippocampal BDNF per se is not sufficient to mediate depression-like behavior. However, these results support the view that BDNF in the DG might be essential in mediating the therapeutic effect of antidepressants.
Adachi
Megumi
M
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Barrot
Michel
M
Autry
Anita E
AE
Theobald
David
D
Monteggia
Lisa M
LM
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D003213:Conditioning, Psychological; D018891:Dentate Gyrus / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005239:Fear; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D005814:Genes, Viral / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D008124:Locomotion / Q000502:physiology
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor