Selective Loss of Brain-Derived Neurotrophic Factor in the Dentate Gyrus Attenuates Antidepressant Efficacy
- Buckley, P. MD
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 (Fig 6).
FIGURE 6.
—The loss of BDNF in the DG attenuates antidepressant responses in the forced swim test. (A–C) Male floxed BDNF mice that received injection with AAV-Cre in the DG or CA1 subregion of the hippocampus display a similar % of immobility in the forced swim test (FST) as compared with AAV-GFP mice (Control). (A) Antidepressant treatment with desipramine significantly reduced immobility time in AAV-GFP mice (p < .05) as well as mice with a selective reduction of BDNF in the CA1 subregion of the hippocampus (p < .05) (AAV-GFP, n = 12; AAV-Cre, n = 11). (B) Desipramine treatment significantly reduced immobility time in AAV-GFP mice (p < .05) but not in the mice with a selective loss of BDNF in the DG (AAV-GFP, n = 12; AAV-Cre, n = 13). (C) With the selective serotonin reuptake inhibitor citalopram, we found that this antidepressant also significantly reduced immobility time in AAV-GFP mice (p = .05) but not in the mice with a selective loss of BDNF in the DG (AAV-GFP, n = 11; AAV-Cre, n = 11). KO, knockout; other abbreviations as in Figure 1. (Reprinted from Adachi M, Barrot M, Autry AE, et al. Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry. 2008;63:642-649, with permission from the Society of Biological Psychiatry.)