@article{RantamaekiVesaAntilaetal.2011,
  author    = {Rantam{\"a}ki, Tomi and Vesa, Liisa and Antila, Hanna and Di Lieto, Antonio and Tammela, P{\"a}ivi and Schmitt, Angelika and Lesch, Klaus-Peter and Rios, Maribel and Castr{\´e}n, Eero},
  title     = {Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade},
  series = {PLoS ONE},
  volume    = {6},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0020567},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133746},
  pages     = {e20567},
  year      = {2011},
  abstract  = {Background: Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. Methodology: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. Principal Findings: Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf(-/-) knock-out mice (132.4+/-8.5\% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. Conclusions: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain.},
  language  = {en}
}
@phdthesis{Araragi2013,
  author    = {Araragi, Naozumi},
  title     = {Electrophysiological investigation of two animal models for emotional disorders - serotonin transporter knockout mice and tryptophan hydroxylase 2 knockout mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-83265},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Serotonin (5-HT) has been implicated in the regulation of emotions as well as in its pathological states, such as anxiety disorders and depression. Mice with targeted deletion of genes encoding various mediators of central serotonergic neurotransmission therefore provides a powerful tool in understanding contributions of such mediators to homeostatic mechanisms as well as to the development of human emotional disorders. Within this thesis a battery of electrophysiological recordings were conducted in the dorsal raphe nucleus (DRN) and the hippocampus of two murine knockout lines with deficient serotonergic systems. Serotonin transporter knockout mice (5-Htt KO), which lack protein responsible for reuptake of 5-HT from the extracellular space and tryptophan hydroxylase 2 knockout (Tph2 KO) mice, which lack the gene encoding the neuronal 5-HT-synthesising enzyme. First, 5-HT1A receptor-mediated autoinhibition of serotonergic neuron firing in the DRN was assessed using the loose-seal cell-attached configuration. Stimulation of 5-HT1A receptors by a selective agonist, R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT), showed a mild sensitisation and a marked desensitisation of these receptors in Tph2 KO and 5-Htt KO mice, respectively. While application of tryptophan, a precursor of 5-HT and a substrate of Tph2, did not cause autoinhibition in Tph2 KO mice due to the lack of endogenously produced 5-HT, data from 5-Htt KO mice as well as heterozygous mice of both KO mice lines demonstrated the presence of autoinhibitory mechanisms as normal as seen in wildtype (WT) controls. When the Tph2-dependent step in the 5-HT synthesis pathway was bypassed by application of 5-hydroxytryptophan (5-HTP), serotonergic neurons of both Tph2 KO and 5-Htt KO mice showed decrease in firing rates at lower concentrations of 5-HTP than in WT controls. Elevated responsiveness of serotonergic neurons from Tph2 KO mice correspond to mild sensitisation of 5-HT1A receptors, while responses from 5-Htt KO mice suggest that excess levels of extracellular 5-HT, created by the lack of 5-Htt, stimulates 5-HT1A receptors strong enough to overcome desensitisation of these receptors. Second, the whole-cell patch clamp recording data from serotonergic neurons in the DRN showed no differences in basic electrophysiological properties between Tph2 KO and WT mice, except lower membrane resistances of neurons from KO mice. Moreover, the whole-cell patch clamp recording from CA1 pyramidal neurons in the hippocampus of 5-Htt KO mice showed increased conductance both at a steady state and at action potential generation. Lastly, magnitude of long-term potentiation (LTP) induced by the Schaffer collateral/commissural pathway stimulation in the ventral hippocampus showed no differences among Tph2 KO, 5-Htt KO, and WT counterparts. Taken together, lack and excess of extracellular 5-HT caused sensitisation and desensitisation of autoinhibitory 5-HT1A receptors, respectively. However, this may not directly translate to the level of autoinhibitory regulation of serotonergic neuron firing when these receptors are stimulated by endogenously synthesised 5-HT. In general, KO mice studied here showed an astonishing level of resilience to genetic manipulations of the central serotonergic system, maintaining overall electrophysiological properties and normal LTP inducibility. This may further suggest existence of as-yet-unknown compensatory mechanisms buffering potential alterations induced by genetic manipulations.},
  subject      = {Serotonin},
  language  = {en}
}