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. This data suggests that the loss of BDNF in either the CA1 or DG subregions of the hippocampus does not alter a broad range of behavioral characteristics. However, BDNF expressed in DG appears to be necessary for mediating antidepressant responses.
In this study, we targeted the knockout of BDNF bilaterally into either the CA1 or DG region of adult male mice. In these animals, the levels of BDNF expression in the CA1 and DG subregions were 52% and 62%, respectively, lower than those from AAV-GFP injected mice. However, within an individual cell that expressed Cre recombinase, BDNF expression was virtually non-existent (data not shown). These data suggest that the loss of BDNF is in effect complete within a cell that is infected with Cre recombinase, however, the AAV is not infecting every cell within the subregion thus the deletion of BDNF was not entirely complete within the area.
The localized deletion of BDNF in either the CA1 or DG does not alter locomotor activity compared to floxed BDNF mice injected with AAV-GFP. This behavioral profile is similar to data obtained from our inducible BDNF KO’s in which we deleted BDNF in adult animals, suggesting that increased locomotor activity reported in heterozygous BDNF mice and conditional BDNF mice is not an acute outcome of BDNF loss, but rather due to a developmental effect (28
). We also did not observe alterations in measures of anxiety-like behavior, which are in agreement with similar findings we obtained with inducible and conditional BDNF KO’s (28
We found normal context and cue dependent fear conditioning following the selective loss of BDNF in the CA1 or DG. This data was somewhat surprising in that we had observed a deficit in context-dependent fear conditioning in the inducible BDNF KO’s (28
) and BDNF has been suggested to play a role in the cellular form of learning and memory, long-term potentiation (LTP) (35
). However, an independent BDNF conditional KO line with a different forebrain deletion pattern did not show alterations in context-dependent fear conditioning although other learning deficits were observed (44
). Closer examination of the role of BDNF in LTP provides a conflicting role of this neurotrophic factor in subregions of the hippocampus. One study demonstrated that BDNF constitutive knockouts have LTP alterations in the Schaffer collateral synapses but that this deficit could be rescued by BDNF overexpression in the CA1 region (45
). In contrast, another group found that the selective loss of BDNF in the CA1 region is not involved in LTP (43
). These data highlight the complex role of BDNF dependent cellular processes in subregions of the hippocampus. However, our ability to detect context-dependent deficits in fear-conditioning in the inducible KO’s and not the AAV selectively targeted deletions in this study, using the same behavioral parameters, suggest that the loss of BDNF selectively in either the DG or CA1 region is not sufficient to mediate deficits in this learning and memory process.
The loss of BDNF selectively in the CA1 or DG did not alter ‘depression-like’ behavior as assessed by the FST and sucrose preference test. This data is in agreement with our previous data showing that broad forebrain loss of BDNF is not sufficient to mediate an increase in depression-like behavior per se
). We used the FST since it has been used to examine depression-like and antidepressant-related behavior in numerous genetic models (46
). We have previously attempted to examine conditional BDNF mice in the learned helplessness paradigm, another animal model to examine depression/antidepressant related responses (29
). Unfortunately, we have not been able to generate a ‘helpless’ response in this mouse line presumably because of the genetic background of the floxed BDNF mice. Therefore, in this study we chose to examine sucrose preference as a model of anhedonia-like behavior. The loss of BDNF in either the CA1 or DG region did not produce alterations in depression-like behavior as assessed by either test. The one caveat is that we were only able to reduce BDNF levels by ~50% in these subregions of the hippocampus so this amount of BDNF reduction may not be sufficient to see deficits in depression-like behavior, although similar data was obtained with inducible and conditional BDNF KO’s which had broad forebrain reductions of 70 and 60% respectively (28
We demonstrated that the loss of BDNF in the DG, but not the CA1 region, attenuates the actions of the antidepressant desipramine, a tricylic that inhibits the reuptake of norepinephrine, or citalopram, a serotonin selective reuptake inhibitor, in the FST. The findings with both desipramine and citalopram suggest that the attenuated response to these antidepressants in the localized DG KO’s is sensitive to both alterations in norepinephrine and serotonin. Results from this study complement and extend previous data showing that the antidepressant effects of BDNF are observed with infusions into the DG granule cell layer but not the CA1 region of the hippocampus suggesting a regional specificity to these behavioral effects (14
). This selective requirement of BDNF in the DG is intriguing and suggests that the actions of this neurotrophic factor are important in the cellular and behavioral aspects of antidepressant responses, at least those mediated by the FST. It is intriguing that the BDNF effect in mediating antidepressant efficacy is specific for the DG, the region of the hippocampus in which antidepressant treatment significantly increases neurogenesis (47
). Accumulating evidence suggests that neurogenesis is important for the behavioral effects of antidepressants (48
). Recent studies have shown that BDNF heterozygous mice or TrkB dominant negative mice have normal cell proliferation but decreased survival of newborn neurons (49
). Future studies will be necessary to assess whether the selective deletion of BDNF in the adult DG impacts survival of newborn neurons as predicted from the previous study.
In summary, we have demonstrated that the selective loss of BDNF in the DG subregion of the hippocampus results in an attenuated response to antidepressants that is not observed following BDNF deletion in the CA1 region. The loss of BDNF in either of these subregions does not alter depression-like behavior, fear conditioning, locomotor activity, or anxiety-related behavior. These results suggest that this growth factor in the DG may be essential for mediating aspects of antidepressant treatment and highlight the regional specificity of this effect.