title: The antidepressant fluoxetine mobilizes vesicles to the recycling pool of rat hippocampal synapses during high activity.
abstract: Effects of the antidepressant fluoxetine in therapeutic concentration on stimulation-dependent synaptic vesicle recycling were examined in cultured rat hippocampal neurons using fluorescence microscopy. Short-term administration of fluoxetine neither inhibited exocytosis nor endocytosis of RRP vesicular membranes. On the contrary, acute application of the drug markedly increased the size of the recycling pool of hippocampal synapses. This increase in recycling pool size was corroborated using the styryl dye FM 1-43, antibody staining with αSyt1-CypHer™5E and overexpression of synapto-pHluorin, and was accompanied by an increase in the frequency of miniature postsynaptic currents. Analysis of axonal transport and fluorescence recovery after photobleaching excluded vesicles originating from the synapse-spanning superpool as a source, indicating that these new release-competent vesicles derived from the resting pool. Super resolution microscopy and ultrastructural analysis by electron microscopy revealed that short-term incubation with fluoxetine had no influence on the number of active synapses and synaptic morphology compared to controls. These observations support the idea that therapeutic concentrations of fluoxetine enhance the recycling vesicle pool size and thus the recovery of neurotransmission from exhausting stimuli. The change in the recycling pool size is consistent with the plasticity hypothesis of the pathogenesis of major depressive disorder as stabilization of the vesicle recycling might be responsible for neural outgrowth and plasticity.
authors.affiliation: Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Jung
authors.forename: Kristina
authors.initials: K
authors.lastname: Loy
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schilling
authors.forename: Mareike
authors.initials: M
authors.lastname: Röther
authors.forename: Jan M
authors.initials: JM
authors.lastname: Brauner
authors.forename: Tobias
authors.initials: T
authors.lastname: Huth
authors.forename: Ursula
authors.initials: U
authors.lastname: Schlötzer-Schrehardt
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.forename: Oliver
authors.initials: O
authors.lastname: Welzel
authors.forename: Teja W
authors.initials: TW
authors.lastname: Groemer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine