Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines.

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.

Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticity-related genes in mouse brain.

Significant body of evidence indicates an important role for brain-derived neurotrophic factor (BDNF) in the hippocampal synaptic plasticity; however, the exact mechanisms how the BDNF signal is converted to plastic changes during memory processes are under an intense investigation. To specifically address the role of the trkB receptor, we have previously generated transgenic mice overexpressing the full-length trkB receptor and observed a continuous activation of the trkB.TK+ receptor, improved learning and memory but an attenuated LTP in these mice. In this study, we describe the trkB.TK+ mRNA and protein distribution in the transgenic mice, showing the most prominent increase in the full-length trkB expression in the cortical layer V pyramidal neurons and dentate gyrus of the hippocampus. In addition, we have analyzed the mRNA expression patterns of a group of genes associated with both plastic changes in the nervous system and BDNF signaling. Regulated expression of immediate early genes c-fos, fra-2 and junB was observed in the transgenic mice. Furthermore, the mRNA expression of alpha-Ca2+/calmodulin-dependent kinase II (alpha-CaMKII) was reduced in both the hippocampus and parietal cortex, whereas growth-associated protein 43 (GAP-43) mRNA expressions were induced in the corresponding regions. Conversely, the mRNA expression of the transcription factor cAMP response element binding protein (CREB) was not altered in the trkB.TK+mice. Finally, the density of neuropeptide Y (NPY)-expressing cells was increased in the trkB.TK+ mice dentate hilus. Altogether, these results demonstrate in vivo that the increased trkB.TK+ signaling regulates several important plasticity-related genes.

Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCgamma pathway, reduced anxiety, and facilitated learning.

We have investigated the biochemical, physiological, and behavioral properties of transgenic mice overexpressing the full-length neurotrophin receptor trkB (trkB.TK+). The highest trkB.TK+ mRNA overexpression was achieved in the cerebral cortex and hippocampal subfields, both areas also showing strongly increased trkB.TK+ receptor protein expression and phosphorylation. Furthermore, as a result of trkB.TK+ overexpression, partial activation of trkB downstream signaling was observed. Phosphorylation of phospholipaseCgamma-1 was increased but unexpectedly, the expression and phosphorylation levels of signaling molecules Shc and mitogen-activated protein kinase (MAPK) were unaltered. Behavioral studies revealed improved learning and memory in the water maze, contextual fear conditioning, and conditioned taste aversion tests, and reduced anxiety in the elevated plus maze (EPM) and light-dark exploration tests in trkB.TK+ transgenic mice. Electrophysiological studies revealed a reduced long-term potentiation (LTP) at the Schaffer collateral-CA1 synapse in trkB.TK+ mice. Altogether, overexpression of the trkB.TK+ receptor postnatally leads to selective activation of trkB signaling pathways and enhanced learning and memory.

Altered trkB neurotrophin receptor activation does not influence the N-methyl-D-aspartate receptor antagonist-mediated neurotoxicity in mouse posterior cingulate cortex.

Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists produce toxic effects in the limbic cortex of rodent brain. NMDA antagonists also increase the expression of brain-derived neurotrophic factor (BDNF) mRNA in the same brain areas. The aim of this study was to investigate whether increased BDNF signalling plays a role in the NMDA-mediated toxic effect by using transgenic mice with modified BDNF signalling and HSP-70 expression as an indicator of toxicity. Neither the enhanced nor the reduced trkB activity influenced MK-801-induced neurotoxic effects in the posterior cingulate cortex of mouse brain, which indicates that increased BDNF production neither protects nor exacerbates neurotoxic effects of NMDA receptor antagonists.

Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects.

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.

BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus.

Both fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) are implicated in the maturation of neurons and in the higher cognitive functions. We have investigated whether FMRP and BDNF are reciprocally regulated in neurons. Exposure of cultured hippocampal neurons to BDNF, but not to NT-3, reduced FMR1 mRNA levels to 84.8% of control at 4 h and the levels were back to baseline by 24 h or 4 days. Furthermore, expression of FMR1 mRNA was reduced (82.4% of control) in vivo in the hippocampus of transgenic mice overexpressing TrkB receptors, and a small but significant (5.1%) decrease was also detected in FMRP protein levels. In contrast, the expression patterns of BDNF and TrkB mRNAs were not altered in FMRP-deficient mice compared to wild-type mice. Our data provide evidence that BDNF via TrkB signaling decreases FMRP expression and suggest a role for FMRP in BDNF-induced synaptic plasticity.

Decreased BDNF signalling in transgenic mice reduces epileptogenesis.

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.