The role of brain-derived neurotrophic factor in the actions of stress and antidepressant treatments

Exposure to severe stress is thought to precipitate and exacerbate depression. The hippocampus is one of the primary targets of stress. Severe stress has damaging influences on hippocampal neurons. Expression of brain-derived neurotrophic factor (BDNF), which influences hippocampal survival, morphology and function, is down-regulated by stress and may contribute to its damaging effects. One aim of this thesis is to examine the cellular mechanisms underlying the stress-induced down-regulation of BDNF. It was found that 5-HT{dollar}sb{lcub}rm 2A{rcub}{dollar} receptors plays an important role in the stress response. Pretreatment with 5-HT{dollar}sb{lcub}rm 2A{rcub}{dollar} receptor antagonists lead to a significant blockade of the stress-induced decrease in BDNF. In addition, activation of the 5-HT{dollar}sb{lcub}rm 2A{rcub}{dollar} receptor results in a significant, but differential regulation of basal BDNF mRNA levels in hippocampus and neocortex.; Previous studies have demonstrated that chronic administration of antidepressants, including electroconvulsive seizure (ECS) treatment, leads to up-regulation of BDNF mRNA and can block the stress-induced decrease in BDNF. A second aim of this thesis is to determine if antidepressants influence hippocampal neuronal morphology. Chronic ECS administration was found to induce sprouting of the mossy fiber pathway in the hippocampus. Moreover, this sprouting occurs in the absence of hilar neuronal loss. Mossy fiber sprouting reaches a maximum 12 days after the last seizure treatment, and appears to be a long-lasting alteration in that six months later there is still significant sprouting. In addition, this study demonstrates that ECS-induced sprouting is significantly diminished in BDNF heterozygote knockout mice. This suggests that ECS-induced BDNF expression may contribute to mossy fiber sprouting. A third aim was to study the cellular proteins that may mediate this sprouting. The results demonstrate that chronic ECS treatment induces alterations in the neurofilament proteins which may underlie ECS-induced structural plasticity. Chronic ECS administration is one of the most effective treatments for depression and its influence on the hippocampus may play a role in its therapeutic actions. The results of this thesis have extended previous work on the role of neurotrophins and adaptations of cellular architecture in the actions of stress and antidepressants.