Adaption of the serotoninergic neuronal phenotype in the absence of 5-HT autoreceptors or the 5-HT transporter: involvement of BDNF and cAMP.
Serotonin 5-HT1A and 5-HT1B receptors and the 5-HT transporter are key regulators of the serotoninergic neuronal phenotype. We show here that genetic deletion of any of these elements differentially regulates 5-HT neuronal number in rostral raphe cultures from E14 mice. Serotonin neuronal number was increased by almost four-fold and 1.8-fold in cultures from 5-HT1AR-/- and 5-HT1BR-/- mice, respectively. In contrast, the lack of serotonin transporter expression was associated with a 50% decrease in 5-HT neuronal number. In raphe cultures from the rat, BDNF and cAMP have been shown to up-regulate the neuronal serotoninergic phenotype through TrkB-dependent mechanisms [Rumajogee et al. (2002) J. Neurochem., 83, 1525-1528]. Similar tyrosine kinase-dependent up-regulating effects, in the absence of serotoninergic key-elements are reported here, on both 5-HT neuronal number and neurites length. However, the extents of BDNF-triggered and cAMP-triggered effects on serotoninergic neuritic length were approximately 1.5-fold higher in 5-HT1AR-/- mutants. These findings show that the up-regulatory mechanisms triggered by BDNF on serotoninergic neuronal number and neurite extension are different and that the latter are partially linked to 5-HT, probably through 5-HT1A autoreceptors. Together, these data suggest that serotonin autoreceptors, mainly 5-HT1A but also 5-HT1B, may be responsible for a tonic auto-inhibitory effect of 5-HT itself on the serotoninergic neuronal phenotype during embryonic development, particularly marked in the absence of the 5-HT transporter.
Laboratoire de Neurobiologie des Signaux Intercellulaires, CNRS UMR 7101, Université Pierre et Marie Curie, 7 quai Saint-Bernard, 75005 Paris, France.
Prakasham
P
Rumajogee
Daniel
D
Vergé
Naïma
N
Hanoun
Marie-Jeanne
MJ
Brisorgueil
René
R
Hen
Klaus-Peter
KP
Lesch
Michel
M
Hamon
Marie-Christine
MC
Miquel
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D017660:Autoreceptors / Q000172:deficiency / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics; D000242:Cyclic AMP / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D011985:Receptors, Serotonin / Q000172:deficiency* / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins
D017660:Autoreceptors; D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D000242:Cyclic AMP