Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

No abstract

1. Neurotrophins and serotonin have both been implicated in the pathophysiology of depression and in the mechanisms of antidepressant treatments. 2. Brain-derived neurotrophic factor (BDNF) influences the growth and plasticity of serotonergic (5-HT) neurons via the activation of trkB receptor. 3. Transgenic mice overexpressing the full-length trkB receptor (TrkB.TK+) and showing increased trkB activity in brain, and their wild type (WT) littermates, were injected with the antidepressant fluoxetine or saline, and analyzed behaviorally in the forced swimming test paradigm and biochemically for the concentrations of brain monoamines and their metabolites. 4. The TrkB.TK+ mice displayed increased latency to immobility in the forced swim test, suggesting resistance to behavioral despair. 5. Fluoxetine increased the latency to immobility in wild-type mice to a similar level as seen in the trkB.TK+ mice after saline treatment, but had no further behavioral effect in the swimming behavior of the trkB.TK+ mice. 6. Only minor differences in the levels of brain monoamines and their metabolites were observed between the transgenic and wild-type mice. 7. These data, together with other recent observations, suggest that trkB activation may play a critical role in the behavioral responses to antidepressant drugs in mice.

Brain derived neurotrophic factor (BDNF) has been suggested to be involved in epileptogenesis. Both pro- and antiepileptogenic effects have been reported, but the exact physiological role is still unclear. Here, we investigated the role of endogenous BDNF in epileptogenesis by using transgenic mice overexpressing truncated trkB, a dominant negative receptor of BDNF. After induction of status epilepticus (SE) by kainic acid, the development of spontaneous seizures was monitored by video-EEG system. Hilar cell loss, and the number of neuropeptide Y immunoreactive cells were studied as markers of cellular damage, and mossy fibre sprouting was investigated as a plasticity marker. Our results show that transgenic mice had significantly less frequent interictal spiking than wild-type mice, and the frequency of spontaneous seizures was lower. Furthermore, compared to wild-type animals, transgenic mice had less severe seizures with later onset and mortality was lower. In contrast, no differences between genotypes were observed in any of the cellular or plasticity markers. Our results suggest that transgenic mice with decreased BDNF signalling have reduced epileptogenesis.

No abstract

No abstract

We have investigated the eects of the truncated trkB receptor isoform T1 (trkB.T1) by transient transfection into mouse N2a neuroblastoma cells. We observed that expression of trkB.T1 leads to a striking change in cell morphology characterized by outgrowth of ®lopodia and processes. A similar morphological response was also observed in SH-SY5Y human neuroblastoma cells and NIH3T3 ®broblasts transfected with trkB.T1. N2a cells lack endogenous expression of trkB isoforms, but express barely detectable amounts of its ligands, brainderived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4). The morphological change was ligand-independent, since addition of exogenous BDNF or NT-4 or blockade of endogenous trkB ligands did not in¯uence this response. Filopodia and process outgrowth was signi®cantly suppressed when full-length trkB.TK+ was cotransfected together with trkB.T1 and this inhibitory eect was blocked by tyrosine kinase inhibitor K252a. Transfection of trkB.T1 deletion mutants showed that the morphological response is dependent on the extracellular, but not the intracellular domain of the receptor. Our results suggest a novel ligand-independent role for truncated trkB in the regulation of cellular morphology.

No abstract