Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects

Abstract

Although neurotrophins have been postulated to have antidepressant properties, their effect on anxiety is not clear. We find that transgenic overexpression of the neurotrophin BDNF has an unexpected facilitatory effect on anxiety-like behavior, concomitant with increased spinogenesis in the basolateral amygdala. Moreover, anxiogenesis and amygdalar spinogenesis are also triggered by chronic stress in control mice but are occluded by BDNF overexpression, thereby suggesting a role for BDNF signaling in stressinduced plasticity in the amygdala. BDNF overexpression also causes antidepressant effects, because transgenic mice exhibit improved performance on the Porsolt forced-swim test and an absence of chronic stress-induced hippocampal atrophy. Thus, structural changes in the amygdala and hippocampus, caused by genetic manipulation of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders.amygdala ͉ chronic stress ͉ hippocampus ͉ morphology ͉ dendritic spines P rolonged and severe stress is associated with various cognitive and affective behavioral abnormalities. The hippocampus, which plays an important role in the formation of declarative memories, has been the primary focus of research on the cognitive effects of chronic stress (1). From a cell biological perspective, a reduction in the length and complexity of dendritic arbors of hippocampal CA3 pyramidal neurons is a well characterized morphological feature of various rodent models of repeated stress (2). This stress-induced dendritic remodeling, in turn, has been hypothesized to underlie the hippocampal volume loss (3, 4) seen in patients suffering from various stress-related disorders, including major depression, Cushing's syndrome, and posttraumatic stress disorder (5-7). Recent evidence has pointed to neurotrophins as a cause for these changes and have led to the ''neurotrophic hypothesis,'' which states that symptoms associated with depression, both pathological and behavioral, are a result of decreased neurotrophic support, and conversely, that increasing neurotrophic support would lead to the resolution of these symptoms (8, 9).Although hippocampal plasticity has, over the years, provided a useful framework for studying the cognitive effects of stress at multiple levels of neural organization, the affective aspects of stress disorders, such as increased anxiety, are likely to involve the amygdala, which plays a pivotal role in processing aversive experiences (10, 11). Interestingly, in contrast to the hippocampus, which inhibits the hypothalamic-pituitary-adrenal (HPA) axis, the amygdala stimulates it (12). In addition, pathological anxiety disorders are associated with an increase in amygdalar volume and output (13-16). Analogously, in rodents, the same chronic immobilization stress (CIS) that causes hippocampal atrophy can elicit dendritic growth in the basolateral amygdala (BLA), as well as enhanced anxiety-like behavior (17-19). These crucial diffe...

Selective lentiviral-mediated suppression of microRNA124a in the hippocampus evokes antidepressants-like effects in rats

“…The current behavioral data are consistent with results showing that in male Sprague-Dawley rats, a bilateral infusion of BDNF (0.25 and 1.0 mg) into the dentate gyrus of the hippocampus increases the swimming behavior in the FST and, therefore produces antidepressant-like phenotype (Shirayama et al, 2002). In addition, Govindarajan and coworkers reported that genetically modified mice overexpressing BDNF in excitatory neurons of the forebrain, including the hippocampus, displayed improved performance in the Porsolt FST (Govindarajan et al, 2006). In contrast, heterozygous (+/À) BDNF mice were resistant to the effects of antidepressants in the FST, indicating that antidepressantinduced behavioral effects require regular BDNF signaling (Lindholm et al, 2012;Saarelainen et al, 2003).…”

Is it time to reassess the BDNF hypothesis of depression?

“…Govindarajan et al 78 reports that mice genetically modified to overexpress BDNF exhibit increased anxiety-like behaviour as well as an increase in spinogenesis of the basolateral amygdala, comparable to that seen in wild-type mice exposed to chronic immobilization stress. Furthermore, the same stress protocol was unable to exacerbate the cellular abnormalities in the transgenic mice, suggesting a role for BDNF in stress-induced plasticity of the amygdala.…”

“…If this is true, these results would provide additional evidence against a causal relationship between reduced brain BDNF levels and depression. However, Govindarajan et al 78 also report that overexpression of BDNF was able to protect mice from stress-induced atrophy of Table 3 Evidence for and against the BDNF hypothesis of depression from studies using genetically altered mice…”

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…They also showed a slight but significant increase in hippocampal neurogenesis. The behavioral pattern of the anxiogenic-like effect and reduced immobility in the FST observed in PDE4BÀ/À mice appears not uncommon; it also occurs in BDNF transgenic mice (Govindarajan et al, 2006) and in rats treated acutely with pentylenetetrazol (Cannizzaro et al, 1993) or fluoxetine (Zienowicz et al, 2006). Thus, the present data suggest that PDE4B plays a role in the anxiogenic-like effects of acute rolipram (Heaslip and Evans, 1995;Imaizumi et al, 1994), which also exerts antidepressant activity.…”