Neurogenic effects of fluoxetine are attenuated in p11 (S100A10) knockout mice.
BACKGROUND
Chronic but not acute treatment with antidepressants increases hippocampal neurogenesis. Because chronic treatment with antidepressants also upregulates p11, we hypothesized that p11 might regulate effects of antidepressants on aspects of neurogenesis.


METHODS
Fluoxetine was administered chronically to wild-type (WT) and p11 knockout (KO) mice. In the neurogenic subgranular zone of hippocampus, the effects of fluoxetine on cell survival were examined with bromodeoxyuridine immunohistochemistry, whereas in the same brains cell proliferation was measured with Ki-67 immunohistochemistry, neurogenesis was measured with doublecortin immunohistochemistry, and apoptosis was measured with activated caspase-3. The behavioral action of fluoxetine was assessed in the novelty suppressed feeding test, which is considered neurogenesis-dependent. The localization of p11 in the dentate gyrus was studied with immunohistochemistry.


RESULTS
Vehicle-treated p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis relative to WT mice. In response to fluoxetine, p11 KO mice have reduced cell proliferation, neurogenesis, cell survival, and cell apoptosis in the subgranular zone of hippocampus when compared with WT littermates. P11 was not expressed in neurogenic cells but in different subtypes of neighboring gamma-aminobutyric acid (GABA)ergic interneurons, which also express serotonin 1B and serotonin 4 receptors. The behavioral effects of fluoxetine in the novelty suppressed feeding test were abolished in p11 KO mice.


CONCLUSIONS
P11 is abundantly expressed in hippocampal GABAergic interneurons. The p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis and an attenuated response to fluoxetine in measures of neurogenesis and in a neurogenesis-dependent behavioral test.
Center for Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Martin
M
Egeland
Jennifer
J
Warner-Schmidt
Paul
P
Greengard
Per
P
Svenningsson
D000704:Analysis of Variance; D000818:Animals; D017306:Annexin A2 / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D005473:Fluoxetine; D009418:S100 Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D005680:gamma-Aminobutyric Acid; D000099248:S100 Calcium Binding Protein A10