Elsevier

Biological Psychiatry

Volume 63, Issue 7, 1 April 2008, Pages 642-649
Biological Psychiatry

Original Article
Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy

https://doi.org/10.1016/j.biopsych.2007.09.019Get rights and content

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.

Section snippets

Floxed BDNF Mice

The floxed BDNF mice have previously been described (32). In prior studies, we crossed these floxed BDNF mice with a neuron-specific enolase (NSE)–tetracycline transactivator (tTA) × tetracycline operator sequences (TetOp)–Cre line to create an inducible deletion of BDNF in the brain as well as a targeted deletion of BDNF in the ventral tegmental area (28, 31). These studies demonstrated that BDNF is only deleted in the presence of Cre recombinase in the floxed mice. For the present study, only

Localized Regional Specific Deletion of BDNF in Hippocampus

We generated a localized selective deletion of the BDNF gene in the CA1 or DG with a floxed BDNF mouse, in which exon 6, the single coding region of the BDNF gene, is flanked by loxP sites (32). The BDNF floxed mice were bilaterally injected with AAV-Cre into CA1 or DG to induce the localized KO. We have previously demonstrated that this AAV-Cre construct mediates recombination in the brain after injection into BDNF floxed mice (31). As a control, floxed BDNF mice received bilateral injections

Discussion

Results of this study demonstrate that the loss of BDNF selectively in the DG results in an attenuation of antidepressant efficacy. In contrast, the selective loss of BDNF in the CA1 subregion of the hippocampus did not alter the response to antidepressants. Mice with a selective loss of BDNF in either the CA1 or DG region of the hippocampus have normal locomotor activity, anxiety-like behavior, fear-conditioning, and depression-like behavior. These data suggest that the loss of BDNF in either

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