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Eero Castrén

Publications and source records attributed to Eero Castrén.

At least 19 recordsLinked to original sources
PubMed2006

Role of neurotrophic factors in depression.

Major depression is associated with reduced volumes in the hippocampus and prefrontal cortex, whereas antidepressant treatments promote several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation, in the hippocampus. Several neurotrophic factors are associated with depression or antidepressant action. Stress suppresses brain-derived neurotrophic factor (BDNF) synthesis in the hippocampus, at least partially through a sustained modification of chromatin structure. Essentially all antidepressant treatments increase BDNF synthesis and signaling in the hippocampus and prefrontal cortex. This signaling is required for the behavioral effects of antidepressant drugs in rodents, and increased BDNF levels in the hippocampus mimic the behavioral effects of antidepressants. However, injection of BDNF into the mesolimbic dopamine pathway produces an opposing depression-like response. One hypothesis emerging from these data proposes that mood disorders reflect failed function of critical neuronal networks, whereas a gradual network recovery through activity-dependent neuronal plasticity induces the antidepressant effect. Neurotrophic factors themselves do not control mood, but they act as necessary tools in the activity-dependent modulation of networks, the physiological function of which determines how a plastic change influences mood.

Animals↗
PubMed2006

Neurotrophins and dementia--keeping in touch.

Down's syndrome patients develop dementia similar to Alzheimer's disease and show elevated levels of amyloid precursor protein in brain. Two papers in this issue of Neuron show that reduced retrograde transport or signaling of the neurotrophins NGF or BDNF, respectively, may account for the neuronal pathology in mouse models of Down's syndrome.

Alzheimer Disease↗
PubMed2006

Phosphoproteomic analysis of neurotrophin receptor TrkB signaling pathways in mouse brain.

1. The signaling pathways activated by trkB neurotrophin receptor have been studied in detail in cultured neurons, but little is known about the pathways activated by trkB in intact brain. TrkB is a tyrosine kinase and protein phosphorylation is a key regulatory process in the neuronal signal transduction pathways. 2. We have investigated trkB signaling in the transgenic mice overexpressing trkB in postnatal neurons (trkB.TK) using phosphoproteomics. 3. We found that several proteins are overphosphorylated on tyrosine residues in the brain of trkB.TK mice and identified some of these proteins. 4. We demonstrate that the well characterized signaling molecules mitogen-activated protein kinase (MAPK) and cyclic AMP responsive element binding protein (CREB) were phosphorylated at a higher level in the brain of trkB.TK mice when compared to the wild type littermates. Furthermore, we found that beta-actin was tyrosine phosphorylated in the brain of the transgenic mice. 5. Our results demonstrate that phosphoproteomics is a sensitive approach to investigate signaling pathways activated in mouse brain.

Animals↗
PubMed2006

Long-term adeno-associated viral vector-mediated expression of truncated TrkB in the adult rat facial nucleus results in motor neuron degeneration.

Adult facial motor neurons continue to express full-length TrkB tyrosine kinase receptor (TrkB.FL), the high-affinity receptor for the neurotrophins BDNF and neurotrophic factor-4/5 (NT-4/5), suggesting that they remain dependent on target-derived and locally produced neurotrophins in adulthood. Studies on the role of TrkB signaling in the adult CNS have been hampered by the early lethality of bdnf, nt-4/5, and trkB knock-out mice. We disrupted TrkB.FL signaling in adult facial motor neurons using adeno-associated viral vector-mediated overexpression of a naturally occurring dominant-negative TrkB receptor, TrkB.T1. Expression of TrkB.T1 resulted in neuronal atrophy and downregulation of NeuN (neuronal-specific nuclear protein) and ChAT expression in facial motor neurons. A subset of transduced neurons displayed signs of motor neuron degeneration that included dendritic beading and rounding of the soma at 2 months of TrkB.T1 expression. Cell counts revealed a significant reduction in motor neuron number in the facial nucleus at 4 months after onset of expression of TrkB.T1, suggesting that a proportion of TrkB.T1-expressing motor neurons became undetectable as a result of severe atrophy or was lost because of cell death. In contrast, overexpression of TrkB.FL did not result in a decrease in facial motor neuron number. Our results indicate that a subset of facial motor neurons remains dependent on TrkB ligands for the maintenance of structural and molecular characteristics in adulthood.

Animals↗
PubMed2006

Overexpression of a truncated TrkB isoform increases the proliferation of neural progenitors.

The truncated isoform of TrkB, TrkB.T1, has been shown to be expressed in the neurogenic region of rodent brain. TrkB.T1 lacks tyrosine kinase activity and it may modify the action of the full-length TrkB. We show here that the full-length TrkB and TrkB.T1 are expressed at the same relative expression levels in mouse neural progenitor cell cultures. The number of neurosphere-forming progenitors was reduced and apoptosis increased in neurospheres generated from mice overexpressing TrkB.T1 when compared with wild-type neurospheres. The proliferation of the transgenic neural progenitors was increased, as indicated by the larger average diameter of spheres (140% of control), the increased cell growth in an MTT assay (137% of control) and the faster rate of 3H-thymidine incorporation (128% of control) in the transgenic cell cultures than in controls. The proliferation of neural progenitors was also increased after lentivirus-mediated TrkB.T1 overexpression. A significant increase in 3H-thymidine incorporation (119% of control) and the average diameter of spheres (112% of control) in the TrkB.T1-transduced neurospheres compared with neurospheres transduced with the control vectors confirmed the role of TrkB.T1 in proliferation of neural progenitor. When induced to differentiate, progenitors overexpressing TrkB.T1 generated two to three times more neurons than did wild-type cells. The increase in the number of neurons correlated with an increase in the number of apoptotic cells (two-fold) at these time points. The data indicate that changes in the relative expression levels of different TrkB isoforms influence the replicative capacity of neural progenitors.

Analysis of Variance↗
PubMed2005

Altered differentiation of neural stem cells in fragile X syndrome.

Fragile X syndrome, a common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein (FMRP) due to a mutation in the FMR1 gene. We investigated the differentiation of neural stem cells generated from the brains of fmr1-knockout (KO) mice and from postmortem tissue of a fragile X fetus. Mouse and human FMRP-deficient neurospheres generated more TuJ1-positive cells (3-fold and 5-fold, respectively) than the control neurospheres generated from normal mouse and human brains, and these cells showed morphological alterations with fewer and shorter neurites and a smaller cell body volume. The number of cells expressing glial fibrillary acidic protein and generated by these neurospheres was reduced because of increased apoptotic cell death. Furthermore, there was an increase in a population of cells with intense oscillatory Ca2+ responses to neurotransmitters in differentiated cells lacking FMRP. In addition, the number of cells in a cohort of bromodeoxyuridine-labeled newborn cells was increased in the subventricular zone of the telencephalon of the fmr1-KO mouse in vivo. These results demonstrate substantial alterations in the early maturation of FMRP-deficient neural stem cells in fragile X syndrome and in the fmr1-KO mice.

Animals↗
PubMed2005

The effects of acute and long-term lithium treatments on trkB neurotrophin receptor activation in the mouse hippocampus and anterior cingulate cortex.

As brain-derived neurotrophic factor (BDNF) and its receptor trkB are linked to the etiology and treatment of mood disorders, we examined the effects of acute and long-term treatment of mood-stabilizer lithium on trkB activation and signaling and BDNF levels in the mouse anterior cingulate cortex (AC) and hippocampus (HC). The trkB activity was measured using specific antibodies against the phosphorylated trkB catalytic domain (pY705/6) and the shc binding site (pY515). In the AC, both acute and long-term LiCl treatment enhanced the pY705/6 of trkB. In contrast, acute or long-term LiCl treatment did not significantly alter the pY705/6 of trkB in the HC. Interestingly, however, acute LiCl treatment significantly reduced the phosphorylation of cAMP related element binding protein (CREB), a major intracellular target of trkB, in the HC. Moreover, pY515 of trkB in the AC and HC was not altered by any of the treatment. Also, prolonged LiCl treatment had no significant effects on BDNF levels or CREB activation in either the AC or HC. The present results suggest that acute and long-term lithium treatment induces trkB activation in the AC but not in the HC. The activation of CREB is, however, significantly reduced in the HC after acute LiCl treatment.

Animals↗
PubMed2005

Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus.

Antidepressants increase proliferation of neuronal progenitor cells and expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. We investigated the role of BDNF signaling in antidepressant-induced neurogenesis by using transgenic mice with either reduced BDNF levels (BDNF+/-) or impaired trkB activation (trkB.T1-overexpressing mice). In both transgenic strains, chronic (21 d) imipramine treatment increased the number of bromodeoxyuridine (BrdU)-positive cells to degree similar to that seen in wild-type mice 24 h after BrdU administration, although the basal proliferation rate was increased in both transgenic strains. Three weeks after BrdU administration and the last antidepressant injection, the amount of newborn (BrdU- or TUC-4-positive) cells was significantly reduced in both BDNF+/- and trkB.T1-overexpressing mice, which suggests that normal BDNF signaling is required for the long-term survival of newborn hippocampal neurons. Moreover, the antidepressant-induced increase in the surviving BrdU-positive neurons seen in wild-type mice 3 weeks after treatment was essentially lost in mice with reduced BDNF signaling. Furthermore, we observed that chronic treatment with imipramine or fluoxetine produced a temporally similar increase in both BrdU-positive and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled neurons in the dentate gyrus, indicating that these drugs simultaneously increase both neurogenesis and neuronal elimination. These data suggest that antidepressants increase turnover of hippocampal neurons rather than neurogenesis per se and that BDNF signaling is required for the long-term survival of newborn neurons in mouse hippocampus.

Animals↗
PubMed2005

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.

Animals↗
PubMed2005

Is mood chemistry?

The chemical hypothesis of depression suggests that mood disorders are caused by a chemical imbalance in the brain, which can be corrected by antidepressant drugs. However, recent evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression, and that antidepressant drugs induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood.

Affect↗
PubMed2004

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.

Animals↗
PubMed2004

Effects of NMDA-receptor antagonist treatment on c-fos expression in rat brain areas implicated in schizophrenia.

1. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists produce behavioral responses that closely resemble both positive and negative symptoms of schizophrenia. These drugs also induce excitatory and neurotoxic effects in limbic cortical areas. 2. We have here mapped the brain areas which show increased activity in response to noncompetitive NMDA-receptor antagonist administration concentrating especially to those brain areas that have been suggested to be relevant in the pathophysiology of schizophrenia. 3. Rats were treated intraperitoneally with a NMDA-receptor antagonist MK801 and activation of brain areas was detected by monitoring the expression of c-fos mRNA by using in situ hybridization. 4. MK801 induced c-fos mRNA expression of in the retrosplenial, entorhinal, and prefrontal cortices. Lower c-fos expression was observed in the layer IV of the parietal and frontal cortex. In the thalamus, c-fos mRNA expression was detected in the midline nuclei and in the reticular nucleus but not in the dorsomedial nucleus. In addition, c-fos mRNA was expressed in the anterior olfactory nucleus, the ventral tegmental area, and in cerebellar granule neurons. 5. NMDA-receptor antagonist ketamine increased dopamine release in the parietal cortex, in the region where NMDA-receptor antagonist increased c-fos mRNA expression. 6. Thus, the psychotropic NMDA-receptor antagonist induced c-fos mRNA expression in most, but not all, brain areas implicated in the pathophysiology of schizophrenia. The high spatial resolution of in situ hybridization may help to define regions of interest for human imaging studies.

Animals↗
PubMed2004

Neurotrophic effects of antidepressant drugs.

The past decade has witnessed a growing interest in the trophic effects of antidepressant drugs. Antidepressants stimulate the production and signaling of plasticity-related proteins such as neurotrophins and cAMP response element binding protein, and neurotrophin signaling appears to be both sufficient and necessary for antidepressant action in rodents. Furthermore, several different antidepressant treatments increase neurogenesis in rodent hippocampus and this effect correlates with the behavioral effects produced by these drugs. These data suggest that antidepressants facilitate activity-dependent selection of functional synaptic connections in brain and, through their neurotrophic effects, improve information processing within neuronal networks compromised in mood disorders.

Animals↗
PubMed2004

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.

Animals↗
PubMed2004

Effects of antidepressant drug imipramine on gene expression in rat prefrontal cortex.

We have investigated gene expression changes produced by acute and chronic daily treatment with a prototypical antidepressant, imipramine, using DNA microarrays. The analysis of similarities in gene expression patterns among functionally related genes revealed four expression profile cluster areas that showed a highly significant overrepresentation of several functional classes. Genes encoding for proteins involved in cAMP metabolism, postsynaptic membrane proteins, and proto-oncogenes were overrepresented in different cluster areas. Furthermore, we found that serine proteases as a group were similarly regulated by chronic antidepressant treatment. Our data suggest that cAMP metabolism, synaptic function, and protein processing by serine proteases may be important targets of antidepressant treatment and potential objects for antidepressant drug development.

Algorithms↗
PubMed2004

Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice.

Brain-derived neurotrophic factor (BDNF) regulates neuronal survival, differentiation and plasticity. It has been shown to promote epileptogenesis and transgenic mice with decreased and increased BDNF signaling show opposite alterations in epileptogenesis. However, the mechanisms of BDNF action are largely unknown. We studied the gene expression changes 12 days after kainic acid-induced status epilepticus in transgenic mice overexpressing either the functional BDNF receptor trkB or a dominant-negative truncated trkB. Epileptogenesis produced marked changes in expression of 27 of 1090 genes. Cluster analysis revealed BDNF signalling-mediated regulation of functional gene classes involved in cellular transport, DNA repair and cell death, including kinesin motor kinesin family member 3A involved in cellular transport. Furthermore, the expression of cytoskeletal and extracellular matrix components, such as tissue inhibitor of metalloproteinase 2 was altered, emphasizing the importance of intracellular transport and interplay between neurons and glia during epileptogenesis. Finally, mice overexpressing the dominant-negative trkB, which were previously shown to have reduced epileptogenesis, showed a decrease in mRNAs of several growth-associated genes, including growth-associated protein 43. Our data suggest that BDNF signaling may partly mediate the development of epilepsy and propose that regrowth or repair processes initiated by status epilepticus and promoted by BDNF signaling may not be as advantageous as previously thought.

Animals↗
PubMed2004

Neurotrophins as mediators of drug effects on mood, addiction, and neuroprotection.

The induction of synthesis or release of endogenous neurotrophic factors in the brain by low-molecular-weight drugs could be a feasible alternative for the direct administration of neurotrophic factors for the treatment of central nervous system disorders. Recent data suggest that several drugs already in clinical use increase the synthesis, release, or signaling of neurotrophins. Antidepressant drugs increase the synthesis and signaling of brain-derived neurotrophic factor (BDNF), and BDNF signaling appears to be both sufficient and necessary for the antidepressant-induced behavioral effects. Furthermore, neurotrophins and other neurotrophic factors play a role in the acute and chronic responses produced by addictive drugs. Moreover, several neuroprotective drugs influence neurotrophin synthesis or signaling, although the significance of these effects is still unclear. These findings reveal a wider role for neurotrophic factors in drug action than has previously been expected, and they suggest that neurotrophin-induced trophic responses in neuronal connectivity and plasticity may be involved in the mechanism of action of several classes of CNS drugs. Improved assay systems are needed for the systematic screening of the effects of putative neuroprotective drugs on the synthesis, release, and signaling of neurotrophic factors, and for the evaluation of the functional role of these factors in the action of novel drug candidates.

Animals↗