title: In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin.
abstract: OBJECTIVE
  We have described a novel antidepressant peptide, spadin, that acts by blocking the TWIK-related-potassium channel, type 1 (TREK-1). Here, we examined possible mechanisms of action of spadin at both molecular and cellular levels.
  
  
  METHODS
  Effects of spadin were measured in primary cultures of neurons or tissues from mice injected i.v. with spadin. Western blots, qPCR, histochemical and electrophysiological techniques were used.
  
  
  RESULTS
  In vitro, spadin increased neuronal membrane potential and activated both the MAPK and PI3K signalling pathways, in a time- and concentration-dependent manner. The latter pathway was involved in the protective effect of spadin against staurosporine-induced apoptosis. Also, spadin enhanced both mRNA expression and protein of two markers of synaptogenesis, the post-synaptic density protein of 95 kDalton (PSD-95) and synapsin. We confirmed these effects on synaptogenesis by the observation that spadin treatment significantly increased the proportion of mature spines in cortical neurons. Finally, in vivo injections of spadin led to a rapid increase in both mRNA expression and protein level of brain-derived neurotrophic factor (BDNF) in the hippocampus, confirming the antidepressant action of the peptide. We argue for a new role of spadin in synaptogenesis as both PSD-95 and synapsin mRNA expression and protein levels were further enhanced in the hippocampus, following treatment in vivo with the peptide.
  
  
  CONCLUSIONS
  These findings provide new mechanisms of action for the rapidly acting antidepressant peptide spadin by stimulating expression of BDNF and synaptic proteins, both in vitro and in vivo.
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Université de Nice-Sophia Antipolis, Valbonne, France.
authors.forename: C
authors.initials: C
authors.lastname: Devader
authors.forename: A
authors.initials: A
authors.lastname: Khayachi
authors.forename: J
authors.initials: J
authors.lastname: Veyssière
authors.forename: H
authors.initials: H
authors.lastname: Moha Ou Maati
authors.forename: M
authors.initials: M
authors.lastname: Roulot
authors.forename: S
authors.initials: S
authors.lastname: Moreno
authors.forename: M
authors.initials: M
authors.lastname: Borsotto
authors.forename: S
authors.initials: S
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Heurteaux
authors.forename: J
authors.initials: J
authors.lastname: Mazella
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000633:toxicity; D013569:Synapses / Q000187:drug effects*; D016704:Synapsins / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D010455:Peptides; D016704:Synapsins; C551795:spadin peptide; D051528:Guanylate Kinases; D019311:Staurosporine